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InternalMed_Harrison. Influenza A viruses also circulate in swine but rarely infect humans. Whereas humans primarily have α-2,6-galactose receptors for hemagglutinins and birds primarily have α-2,3-galactose receptors, swine have both types of receptors. Thus, swine hosts efficiently sustain simultaneous infection with both human and avian viruses, thereby facilitating reassortment of genetic segments between viruses of both species. The pandemic A/H1N1 strain of 2009–2010 was a quadruple reassortant among swine, avian, and human influenza viruses. The influenza A virus subtypes that circulate most commonly in swine are H1N1, H1N2, and H3N2. When a predominantly swine virus causes infections in humans, it is designated a variant virus by the addition of “v” after the subtype. For example, influenza A/H3N2v virus was responsible for 321 cases of human infection reported in the United States in 2011 and 2012 and for 18 cases in 2013. Almost all of the affected patients had had close contact with swine. Only


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InternalMed_Harrison. was responsible for 321 cases of human infection reported in the United States in 2011 and 2012 and for 18 cases in 2013. Almost all of the affected patients had had close contact with swine. Only limited person-to-person transmission of swine influenza virus has been noted. Since 2005, 16 human cases caused by A/H1N1v virus and 5 caused by A/H1N2v virus have been detected in the United States.


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InternalMed_Harrison. Influenza B and C Viruses Influenza B virus causes outbreaks that are generally less extensive and are associated with less severe disease than those caused by influenza A virus, although the disease may occasionally be severe. The hemagglutinin and neuraminidase of influenza B viruses undergo less frequent and less extensive variation than those of influenza A viruses; this characteristic may account, in part, for the lesser severity of influenza B. Outbreaks of influenza B occur most frequently in schools and military camps, although outbreaks in institutions in which elderly individuals reside have also been noted on occasion. Since the 1980s, two antigenically distinct “lineages” of influenza B virus have circulated: Victoria and Yamagata.


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InternalMed_Harrison. In contrast to influenza A and B viruses, influenza C virus appears to be a relatively minor cause of disease in humans. It has been associated with common cold–like symptoms and occasionally with lower respiratory tract illness. The widespread prevalence of serum antibody to this virus indicates that asymptomatic infection may be common.


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InternalMed_Harrison. Influenza-Associated Morbidity and Mortality Rates Rates of morbidity and mortality caused by influenza outbreaks continue to be substantial. Most individuals who die in this setting have underlying diseases that place them at high risk for complications of influenza (Table 224-2). On average, there were 226,000 influenza-associated hospitalizations per year in the United States in 1979–2001. Recently, the moderately severe influenza season in 2012–2013 was associated with 381,500 hospitalizations (42 per 100,000 persons). Excess annual hospitalizations for groups of adults and children with high-risk medical conditions ranged from 40 to 1900 per 100,000 during outbreaks of influenza in 1973–2004. The most prominent high-risk conditions are chronic cardiac and pulmonary diseases and old age. Mortality rates among individuals with chronic metabolic or renal diseases or certain immunosuppressive diseases have also been elevated, although they remain lower than mortality rates among


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InternalMed_Harrison. age. Mortality rates among individuals with chronic metabolic or renal diseases or certain immunosuppressive diseases have also been elevated, although they remain lower than mortality rates among patients with chronic cardiopulmonary diseases. In the pandemic of 2009–2010, increased risk of severe disease was noted in children from birth to 4 years of age and in pregnant women. The morbidity rate attributable to influenza in the general population is considerable. It is estimated that interpandemic outbreaks of influenza currently incur annual economic costs of more than $87 billion in the United States. For pandemics, it is estimated that annual economic costs would range from $89.7 to $209.4 billion for attack rates of 15–35%.


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InternalMed_Harrison. The initial event in influenza is infection of the respiratory epithelium with influenza virus acquired from respiratory secretions of acutely infected individuals. In all likelihood, the virus is transmitted via aerosols generated by coughs and sneezes, although transmission through hand-to-hand contact, other personal contact, and even fomites may take place. Experimental evidence suggests that infection by a small-particle aerosol (particle diameter <10 μm) is more efficient than All children from birth to <5 years, especially <2 years All persons ≥50 years old Pregnant women Adults and children who have chronic pulmonary (including asthma) or car diovascular (except isolated hypertension), renal, hepatic, neurologic, hema tologic, or metabolic disorders (including diabetes mellitus) Persons who have immunosuppression (including that caused by medications or by HIV infection)


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InternalMed_Harrison. Children and adolescents (6 months to 18 years old) who are receiving longterm aspirin therapy and who might be at risk for Reye’s syndrome after influenza virus infection


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InternalMed_Harrison. Residents of nursing homes and other long-term care facilities Native Americans/Alaska Natives Persons who are morbidly obese (body mass index ≥40 kg/m2) that by larger droplets. Initially, viral infection involves the ciliated 1211 columnar epithelial cells, but it may also involve other respiratory tract cells, including alveolar cells, mucous gland cells, and macrophages. In infected cells, virus replicates within 4–6 h, after which infectious virus is released to infect adjacent or nearby cells. In this way, infection spreads from a few foci to a large number of respiratory cells over several hours. In experimentally induced infection, the incubation period of illness has ranged from 18 to 72 h, depending on the size of the viral inoculum. Histopathologic study reveals degenerative changes, including granulation, vacuolization, swelling, and pyknotic nuclei in infected ciliated cells. The cells eventually become necrotic and desquamate; in some areas, previously columnar


InternalMed_Harrison

InternalMed_Harrison. changes, including granulation, vacuolization, swelling, and pyknotic nuclei in infected ciliated cells. The cells eventually become necrotic and desquamate; in some areas, previously columnar epithelium is replaced by flattened and metaplastic epithelial cells. The severity of illness is correlated with the quantity of virus shed in secretions; thus, the degree of viral replication itself may be an important factor in pathogenesis. Despite the frequent development of systemic signs and symptoms such as fever, headache, and myalgias, influenza virus has only rarely been detected in extrapulmonary sites (including the bloodstream). Evidence suggests that the pathogenesis of systemic symptoms in influenza may be related to the induction of certain cytokines, particularly tumor necrosis factor α, interferon α, interleukin 6, and interleukin 8, in respiratory secretions and in the bloodstream.


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InternalMed_Harrison. The host response to influenza infections involves a complex interplay of humoral antibody, local antibody, cell-mediated immunity, interferon, and other host defenses. Serum antibody responses, which can be detected by the second week after primary infection, are measured by a variety of techniques: hemagglutination inhibition (HI), complement fixation (CF), neutralization, enzyme-linked immunosorbent assay (ELISA), and antineuraminidase antibody assay. Antibodies to the hemagglutinin appear to be the most important mediators of immunity; in several studies, HI titers of ≥40 have been associated with protection from infection. Secretory antibodies produced in the respiratory tract are predominantly of the IgA class, and secretory antibody neutralization titers of ≥4 have also been associated with protection. A variety of cell-mediated immune responses, both antigen-specific and antigen-nonspecific, can be detected early after infection and depend on the prior immune status of the


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InternalMed_Harrison. with protection. A variety of cell-mediated immune responses, both antigen-specific and antigen-nonspecific, can be detected early after infection and depend on the prior immune status of the host. These responses include T cell proliferative, T cell cytotoxic, and natural killer cell activity. In humans, CD8+ as well as CD4+ T lymphocytes are directed at conserved regions of internal proteins (NP, M, and P) as well as at the surface proteins H and N. Interferons can be detected in respiratory secretions shortly after the shedding of virus has begun, and rises in interferon titers coincide with decreases in virus shedding.


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InternalMed_Harrison. The host defense factors responsible for cessation of virus shedding and resolution of illness have not been defined specifically. Virus shedding generally stops within 2–5 days after symptoms first appear, at a time when serum and local antibody responses often are not detectable by conventional techniques, although antibody rises may be detected earlier by use of highly sensitive techniques, particularly in individuals with previous immunity to the virus. It has been suggested that interferon, cell-mediated immune responses, and/or nonspecific inflammatory responses all contribute to the resolution of illness. CD8+ cytotoxic T lymphocyte responses may be particularly important in this regard.


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InternalMed_Harrison. Influenza is most frequently described as a respiratory illness characterized by systemic symptoms, such as headache, feverishness, chills, myalgia, and malaise, as well as accompanying respiratory tract signs and symptoms, particularly cough and sore throat. In some cases, the onset is so abrupt that patients can recall the precise time they became ill. However, the spectrum of clinical presentations is wide, ranging from a mild, afebrile respiratory illness similar to the common cold (with either a gradual or an abrupt onset) to severe prostration with relatively few respiratory signs and symptoms. In most of the cases that come to a physician’s attention, the patient has a fever, with temperatures of 38°–41°C (100.4°–105.8°F). A rapid temperature rise within the first 24 h of illness is generally followed by gradual defervescence over 2–3 days, although, on occasion, fever may last as long as 1 week.


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InternalMed_Harrison. 1212 Patients report a feverish feeling and chilliness, but true rigors are rare. Headache, either generalized or frontal, is often particularly troublesome. Myalgias may involve any part of the body but are most common in the legs and lumbosacral area. Arthralgias may also develop. Respiratory symptoms often become more prominent as systemic symptoms subside. Many patients have a sore throat or persistent cough, which may last for ≥1 week and which is often accompanied by substernal discomfort. Ocular signs and symptoms include pain on motion of the eyes, photophobia, and burning of the eyes. In the elderly, influenza may have a relatively subtle presentation. Typical features such as sore throat, myalgia, and even fever may be absent, and general symptoms such as anorexia, malaise, weakness, and dizziness may predominate. Physical findings are usually minimal in uncomplicated influenza. Early in the illness, the patient appears flushed, and the skin is hot and dry, although


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InternalMed_Harrison. weakness, and dizziness may predominate. Physical findings are usually minimal in uncomplicated influenza. Early in the illness, the patient appears flushed, and the skin is hot and dry, although diaphoresis and mottled extremities are sometimes evident, particularly in older patients. Examination of the pharynx may yield surprisingly unremarkable results despite a severe sore throat, but injection of the mucous membranes and postnasal discharge are apparent in some cases. Mild cervical lymphadenopathy may be noted, especially in younger individuals. The results of chest examination are largely negative in uncomplicated influenza, although rhonchi, wheezes, and scattered rales have been reported with variable frequency in different outbreaks. Frank dyspnea, hyperpnea, cyanosis, diffuse rales, and signs of consolidation are indicative of pulmonary complications. Patients with apparently uncomplicated influenza have been reported to have a variety of mild ventilatory defects and


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InternalMed_Harrison. rales, and signs of consolidation are indicative of pulmonary complications. Patients with apparently uncomplicated influenza have been reported to have a variety of mild ventilatory defects and increased alveolar-capillary diffusion gradients; thus, subclinical pulmonary involvement may be more common than is appreciated. In uncomplicated influenza, the acute illness generally resolves over 2–5 days, and most patients have largely recovered in 1 week, although cough may persist 1–2 weeks longer. In a significant minority (particularly the elderly), however, symptoms of weakness or lassitude (postinfluenza asthenia) may persist for several weeks and may prove troublesome for persons who wish to resume their full level of activity promptly. The pathogenetic basis for this asthenia is unknown, although pulmonary function abnormalities may persist for several weeks after uncomplicated influenza.


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InternalMed_Harrison. Complications of influenza occur most frequently in patients >65 years old and in those with certain chronic disorders, including cardiac or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and immunosuppression. Pregnancy in the second or third trimester predisposes to complications with influenza. Children <5 years old (especially infants) are also at high risk for complications (Table 224-2). Pulmonary Complications • pneUmonia The most significant complication of influenza is pneumonia: “primary” influenza viral pneumonia, secondary bacterial pneumonia, or mixed viral and bacterial pneumonia (discussed below).


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InternalMed_Harrison. primary influenza viral pneumonia Primary influenza viral pneumonia is the least common but most severe of the pneumonic complications. It presents as acute influenza that does not resolve but instead progresses relentlessly, with persistent fever, dyspnea, and eventual cyanosis. Sputum production is generally scanty, but the sputum can contain blood. Few physical signs may be evident early in the illness. In more advanced cases, diffuse rales may be noted, and imaging findings consistent with diffuse interstitial infiltrates and/or acute respiratory distress syndrome may be present. In such cases, arterial blood-gas determinations show marked hypoxia. Viral cultures of respiratory secretions and lung parenchyma, especially if samples are taken early in illness, yield high titers of virus. In fatal cases of primary viral pneumonia, histopathologic examination reveals a marked inflammatory reaction in the alveolar septa, with edema and infiltration by lymphocytes, macrophages,


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InternalMed_Harrison. of virus. In fatal cases of primary viral pneumonia, histopathologic examination reveals a marked inflammatory reaction in the alveolar septa, with edema and infiltration by lymphocytes, macrophages, occasional plasma cells, and variable numbers of neutrophils. Fibrin thrombi in alveolar capillaries, along with necrosis and hemorrhage, have also been noted. Eosinophilic hyaline membranes can be found lining alveoli and alveolar ducts.


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InternalMed_Harrison. Primary influenza viral pneumonia has a predilection for individuals with cardiac disease, particularly those with mitral stenosis, but has also been reported in otherwise-healthy young adults as well as in older individuals with chronic pulmonary disorders. In some pandemics of influenza (notably those of 1918 and 1957), pregnancy increased the risk of primary influenza pneumonia. Subsequent epidemics of influenza have been associated with increased rates of hospitalization among pregnant women, which were also noted in the pandemic of 2009–2010.


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InternalMed_Harrison. secondary bacterial pneumonia Secondary bacterial pneumonia follows acute influenza. Improvement of the patient’s condition over 2–3 days is followed by a reappearance of fever along with clinical signs and symptoms of bacterial pneumonia, including cough, production of purulent sputum, and physical and x-ray signs of consolidation. The most common bacterial pathogens in this setting are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae— organisms that can colonize the nasopharynx and that cause infection in the wake of changes in bronchopulmonary defenses. Secondary bacterial pneumonia occurs most frequently in high-risk individuals with chronic pulmonary and cardiac disease and in elderly individuals. Patients with secondary bacterial pneumonia often respond to appropriate antibiotic therapy when it is instituted promptly.


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InternalMed_Harrison. mixed viral and bacterial pneumonia Perhaps the most common pneumonic complications during outbreaks of influenza have mixed features of viral and bacterial pneumonia. Patients may experience a gradual progression of their acute illness or may show transient improvement followed by clinical exacerbation, with eventual manifestation of the clinical features of bacterial pneumonia. Sputum cultures may contain both influenza A virus and one of the bacterial pathogens described above. Patchy infiltrates or areas of consolidation may be detected by physical examination and chest x-ray. Patients with mixed viral and bacterial pneumonia generally have less widespread involvement of the lung than those with primary viral pneumonia, and their bacterial infections may respond to appropriate antibacterial drugs. Mixed viral and bacterial pneumonia occurs primarily in patients with chronic cardiovascular and pulmonary diseases.


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InternalMed_Harrison. otHer pUlmonary complications Other pulmonary complications associated with influenza include worsening of chronic obstructive pulmonary disease and exacerbation of chronic bronchitis and asthma. In children, influenza infection may present as croup. Sinusitis and otitis media (the latter occurring particularly often in children) may also be associated with influenza.


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InternalMed_Harrison. Extrapulmonary Complications Myositis, rhabdomyolysis, and myoglobinuria are occasional complications of influenza infection. Although myalgias are exceedingly common in influenza, true myositis is rare. Patients with acute myositis have exquisite tenderness of the affected muscles, most commonly in the legs, and may not be able to tolerate even the slightest pressure, such as the touch of bedsheets. In the most severe cases, there is frank swelling and bogginess of muscles. Serum levels of creatine phosphokinase and aldolase are markedly elevated, and an occasional patient develops renal failure from myoglobinuria. The pathogenesis of influenza-associated myositis is also unclear, although the presence of influenza virus in affected muscles has been reported.


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InternalMed_Harrison. Myocarditis and pericarditis were reported in association with influenza virus infection during the 1918–1919 pandemic; these reports were based largely on histopathologic findings, and these complications have been reported only infrequently since that time. Electrocardiographic changes during acute influenza are common among patients who have cardiac disease but have been ascribed most often to exacerbations of the underlying cardiac disease rather than to direct involvement of the myocardium with influenza virus. Epidemiologic data have shown an association between influenza outbreaks and increased cardiovascular-associated hospitalizations.


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InternalMed_Harrison. Central nervous system (CNS) complications such as encephalitis and transverse myelitis have been associated with influenza. Encephalitis is a rare but potentially serious complication that has been reported with influenza A and B virus infections. Children <5 years of age appear to be at greatest risk. The pathogenetic mechanisms by which influenza causes CNS disease are unclear. Guillain-Barré syndrome has been reported following influenza infection and, uncommonly, after influenza vaccination (see “Prophylaxis,” below). Toxic shock syndrome associated with S. aureus or group A streptococcal infection following acute influenza infection has been described (Chaps. 172 and 173).


InternalMed_Harrison

InternalMed_Harrison. Toxic shock syndrome associated with S. aureus or group A streptococcal infection following acute influenza infection has been described (Chaps. 172 and 173). Reye’s syndrome is a serious complication in children that is associated with influenza B and—to a lesser extent—influenza A virus infection as well as with varicella-zoster virus and other viral infections. An epidemiologic association between Reye’s syndrome and aspirin therapy for the antecedent viral infection has been noted; the syndrome’s incidence has decreased markedly with widespread warnings regarding aspirin use by children with acute viral respiratory infections.


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InternalMed_Harrison. In addition to complications involving the specific organ systems described above, influenza outbreaks include cases in which elderly and other high-risk individuals develop influenza and subsequently experience a gradual deterioration of underlying cardiovascular, pulmonary, or renal function—changes that occasionally are irreversible and lead to death. These deaths contribute to the overall excess mortality associated with influenza outbreaks.


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InternalMed_Harrison. During acute influenza, virus may be detected in throat swabs, nasopharyngeal swabs or washes, or sputum. Reverse-transcriptase polymerase chain reaction (RT-PCR) is the most sensitive and specific technique for detection of influenza viruses. RT-PCR can differentiate among influenza subtypes and is used for detection of avian influenza viruses. Rapid influenza diagnostic tests (RIDTs) detect influenza virus antigens by immunologic or enzymatic techniques. RIDTs yield results quickly, and some tests can distinguish between influenza A and B viruses. Although relatively specific, RIDTs vary in sensitivity with the technique and the virus to be detected.


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InternalMed_Harrison. Influenza virus may be isolated from tissue culture or chick embryos, but these labor-intensive procedures generally are no longer used for diagnostic purposes. Serologic methods for diagnosis require comparison of antibody titers in sera obtained during the acute illness with those in sera obtained 10–14 days after the onset of illness and are useful primarily in retrospect and for epidemiologic studies. Other laboratory tests generally are not helpful in the specific diagnosis of influenza virus infection. Leukocyte counts are variable, frequently being low early in illness and normal or slightly elevated later. Severe leukopenia has been described in overwhelming viral or bacterial infection, whereas leukocytosis with >15,000 cells/μL raises the suspicion of secondary bacterial infection.


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InternalMed_Harrison. During a community-wide outbreak, a clinical diagnosis of influenza can be made with a high degree of certainty in patients who present to a physician’s office with the typical febrile respiratory illness described above. In the absence of an outbreak (i.e., in sporadic or isolated cases), influenza may be difficult to differentiate on clinical grounds alone from an acute respiratory illness caused by any of a variety of respiratory viruses or by Mycoplasma pneumoniae. Severe streptococcal pharyngitis or early bacterial pneumonia may mimic acute influenza, although bacterial pneumonias generally do not run a self-limited course. Purulent sputum in which a bacterial pathogen can be detected by Gram’s staining is an important diagnostic feature in bacterial pneumonia.


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InternalMed_Harrison. (See also Chap. 215e) Specific antiviral therapy is available for influenza (Table 224-3): the neuraminidase inhibitors zanamivir and oseltamivir for both influenza A and influenza B and the adamantane agents amantadine and rimantadine for influenza A. The epidemiologic patterns of resistance to the influenza antiviral drugs are crucial elements in the selection of treatment. Up-to-date information on patterns of resistance to influenza antiviral drugs is available through www.cdc.gov/flu.


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InternalMed_Harrison. A 5-day course of oseltamivir or zanamivir reduces the duration of signs and symptoms of uncomplicated influenza by 1–1.5 days if treatment is started within 2 days of the onset of illness and may be effective if started up to 5 days after onset of symptoms. Zanamivir is administered via an oral inhalation device and may exacerbate bronchospasm in asthmatic patients. Oseltamivir has been associated with nausea and vomiting, whose frequency can be reduced by administration of the drug with food. Oseltamivir has also been associated with neuropsychiatric side effects in children. Peramivir, an investigational neuraminidase inhibitor that can be administered intravenously, is being evaluated in clinical trials, as is an intravenous form of zanamivir.


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InternalMed_Harrison. Amantadine and rimantadine are active only against influenza A, and widespread resistance exists among influenza A/H1N1 and A/ H3N2 viruses that are circulating currently; thus, the use of these drugs is not recommended unless influenza isolates are known to be sensitive. Amantadine or rimantadine treatment of illness caused by sensitive strains of influenza A virus reduces the duration of symptoms of uncomplicated influenza by ~50% if begun within 48 h after onset of illness—an effect similar to that of the neuraminidase inhibitors. Of amantadine recipients, 5–10% experience mild Treatment, influenza A Not approved 100 mg PO bid 100–200 mg/d


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InternalMed_Harrison. Treatment, influenza A Not approved 100 mg PO bid 100–200 mg/d Prophylaxis, influenza A Age 1–9, 5 mg/kg in 2 divided doses, Age ≥10, 100 mg PO bid 100–200 mg/d up to 150 mg/d a<15 kg: 30 mg bid; >15–23 kg: 45 mg bid; >23–40 kg: 60 mg bid; >40 kg: 75 mg bid. For children <1 year of age, see www.cdc.gov/h1n1flu/recommendations.htm. b<15 kg: 30 mg qd; >15–23 kg: 45 mg qd; >23–40 kg: 60 mg qd; >40 kg: 75 mg qd. For children <1 year of age, see www.cdc.gov/h1n1flu/recommendations.htm. cAmantadine and rimantadine are not currently recommended (2013–2014) because of widespread resistance in influenza A viruses. Their use may be reconsidered if viral susceptibility is reestablished.


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InternalMed_Harrison. 1214 CNS side effects, primarily jitteriness, anxiety, insomnia, or difficulty concentrating. These side effects disappear promptly upon cessation of therapy. Rimantadine appears to be equally efficacious and is associated with less frequent CNS side effects than is amantadine. Ribavirin is a nucleoside analogue with activity against influenza A and B viruses in vitro. Its efficacy against influenza when administered as an aerosol is reportedly variable, and it is ineffective when administered orally. Its efficacy in the treatment of influenza A or B has not been established. The therapeutic efficacy of antiviral compounds in influenza has been demonstrated primarily in studies of young adults with uncomplicated disease. The effectiveness of these drugs in the treatment or prevention of complications of influenza is unclear. Pooled analyses of observational investigations and some efficacy studies have suggested that treatment with oseltamivir may reduce the frequency of lower


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InternalMed_Harrison. of complications of influenza is unclear. Pooled analyses of observational investigations and some efficacy studies have suggested that treatment with oseltamivir may reduce the frequency of lower respiratory complications and hospitalization. Therapy for primary influenza pneumonia is directed at maintaining oxygenation and is most appropriately undertaken in an intensive care unit, with aggressive respiratory and hemodynamic support as needed. Antibacterial drugs should be reserved for the treatment of bacterial complications of acute influenza, such as secondary bacterial pneumonia. The choice of antibiotics should be guided by Gram’s staining and culture of appropriate specimens of respiratory secretions, such as sputum. If the etiology of a case of bacterial pneumonia is unclear from an examination of respiratory secretions, empirical antibiotics effective against the most common bacterial pathogens in this setting (S. pneumoniae, S. aureus, and


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InternalMed_Harrison. H. influenzae) should be selected (Chaps. 171, 172, and 182). For uncomplicated influenza in individuals at low risk of complications, symptom-based rather than antiviral therapy may be considered. Acetaminophen or nonsteroidal anti-inflammatory agents can be used for relief of headache, myalgia, and fever, but salicylates should be avoided in children <18 years of age because of the possible association with Reye’s syndrome (see “Extrapulmonary Complications,” above). Because cough is ordinarily self-limited, treatment with cough suppressants generally is not indicated; codeine-containing compounds may be used if the cough is particularly troublesome. Patients should be advised to rest and maintain hydration during acute illness and to return to full activity only gradually after illness has resolved, especially if it has been severe.


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InternalMed_Harrison. The major public health measure for prevention of influenza is vaccination. Both inactivated (killed) and live attenuated vaccines are available and are generated from isolates of influenza A and B viruses that circulated in the previous influenza seasons and are anticipated to circulate in the upcoming season. For inactivated vaccines, 50–80% protection against influenza is expected if the vaccine virus and the currently circulating viruses are closely related. Available inactivated vaccines have been highly purified and are associated with few reactions. Up to 5% of individuals experience low-grade fever and mild systemic symptoms 8–24 h after vaccination, and up to one-third develop mild redness or tenderness at the vaccination site. Although the 1976 swine influenza vaccine appears to have been associated with an increased frequency of Guillain-Barré syndrome, influenza vaccines administered since 1976 generally have not been. Possible exceptions were noted during the 1992–1993


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InternalMed_Harrison. to have been associated with an increased frequency of Guillain-Barré syndrome, influenza vaccines administered since 1976 generally have not been. Possible exceptions were noted during the 1992–1993 and 1993–1994 influenza seasons, when there may have been an excess risk of this syndrome (slightly more than 1 case per 1 million vaccine recipients). Large-scale studies of vaccination with the 2009 pandemic H1N1 vaccine also suggested a possible increased risk of Guillain-Barré syndrome (1 case per 1 million vaccinees). However, the overall health risk following influenza substantially outweighs the potential risk associated with vaccination.


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InternalMed_Harrison. A live attenuated influenza vaccine administered by intranasal spray is available. The vaccine is generated by reassortment between currently circulating strains of influenza A and B viruses and a cold-adapted, attenuated master strain. The cold-adapted vaccine is well tolerated and highly efficacious (>90% protective) in young children; in one study, it provided protection against a circulating influenza virus that had drifted antigenically away from the vaccine strain. Live attenuated vaccine is approved for use in healthy nonpregnant persons 2–49 years of age.


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InternalMed_Harrison. Since 1975, influenza vaccines have been trivalent—i.e., they have contained two influenza A subtypes (H3N2 and H1N1) and one influenza B component. However, two antigenically distinct lineages of influenza B virus have circulated since the 1980s, and a quadrivalent vaccine that includes both B lineages is now available (2013–2014) as well. Quadrivalent vaccines are available in both inactivated and live-attenuated vaccine formulations. Inactivated influenza vaccines have been noted to be less immunogenic in the elderly. A higher-dose trivalent vaccine containing 60 μg of each antigen and a lower-dose, intradermally administered trivalent vaccine containing 9 μg of each antigen have been approved for use in individuals ≥65 years of age and individuals 18–64 years of age, respectively.


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InternalMed_Harrison. The influenza vaccines discussed above are manufactured in eggs and should not be administered to persons with true hypersensitivity to eggs. For use in this situation, an egg-free vaccine manufactured in cells through recombinant DNA techniques (Flublok®; Protein Sciences Corporation, Meriden, CT) has been approved. Active research is under way to develop vaccines with broad activity against antigenically distinct subtypes (“universal influenza vaccines”).


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InternalMed_Harrison. Historically, the U.S. Public Health Service has recommended influenza vaccination for certain groups at high risk for complications of influenza on the basis of age or underlying disease (Table 224-2) or for their close contacts. Although such individuals will continue to be the focus of vaccination programs, the recommendations have been progressively expanded, and immunization of the entire population above the age of 6 months has been recommended since 2010–2011. (Approved influenza vaccines are not available for infants <6 months of age.) This expanded recommendation reflects increased recognition of previously unappreciated risk factors (e.g., obesity, postpartum conditions, and racial or ethnic influences) as well as an appreciation that more widespread use of vaccine is required for influenza control. Inactivated vaccines may be administered safely to immunocompromised patients. Influenza vaccination is not associated with exacerbations of chronic nervous system diseases such


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InternalMed_Harrison. influenza control. Inactivated vaccines may be administered safely to immunocompromised patients. Influenza vaccination is not associated with exacerbations of chronic nervous system diseases such as multiple sclerosis. Vaccine should be administered early in the autumn before influenza outbreaks occur and should then be given annually to maintain immunity against the most current influenza virus strains.


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InternalMed_Harrison. Although antiviral drugs provide chemoprophylaxis against influenza, their use for that purpose has been limited because of concern about current and future development of resistance. Chemoprophylaxis with oseltamivir or zanamivir has been 84–89% efficacious against influenza A and B (Table 224-3). Chemoprophylaxis with amantadine or rimantadine is no longer recommended because of widespread resistance to these drugs. In earlier studies with sensitive viruses, prophylaxis with amantadine or rimantadine was 70–100% effective against illness associated with influenza A virus.


InternalMed_Harrison

InternalMed_Harrison. Chemoprophylaxis for healthy persons after community exposure generally is not recommended but may be considered for individuals at high risk of complications who have had close contact with an acutely ill person with influenza. During an outbreak, antiviral chemoprophylaxis can be administered simultaneously with inactivated vaccine because the drugs do not interfere with an immune response to the vaccine. However, concurrent administration of chemoprophylaxis and live attenuated vaccine may interfere with the immune response to the latter. Antiviral drugs should not be administered until at least 2 weeks after administration of live vaccine, and administration of live vaccine should not begin until at least 48 h after antiviral drug administration has been stopped. Chemoprophylaxis may also be considered to control nosocomial outbreaks of influenza. For that purpose, prophylaxis should be instituted promptly when influenza activity is detected and must be continued daily for the


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InternalMed_Harrison. also be considered to control nosocomial outbreaks of influenza. For that purpose, prophylaxis should be instituted promptly when influenza activity is detected and must be continued daily for the duration of the outbreak.


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InternalMed_Harrison. 225e-1 The Human Retroviruses Dan L. Longo, Anthony S. Fauci The retroviruses, which make up a large family (Retroviridae), infect mainly vertebrates. These viruses have a unique replication cycle whereby their genetic information is encoded by RNA rather than DNA. Retroviruses contain an RNA-dependent DNA polymerase STRUCTURE AND LIFE CYCLE All retroviruses are similar in structure, genome organization, and mode of replication. Retroviruses are 70–130 nm in diameter and have a lipid-containing envelope surrounding an icosahedral capsid with a dense inner core. The core contains two identical copies of the single-strand RNA genome. The RNA molecules are 8–10 kb long and are complexed with reverse transcriptase and tRNA. Other viral proteins, such as integrase, are also components of the virion particle. The RNA has features usually found in mRNA: a cap site at the 5′ end of the mol-ecule, which is important in the initiation of mRNA translation, and 225e SECTion 14 infECTionS DuE To


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InternalMed_Harrison. virion particle. The RNA has features usually found in mRNA: a cap site at the 5′ end of the mol-ecule, which is important in the initiation of mRNA translation, and 225e SECTion 14 infECTionS DuE To HumAn immunoDEfiCiEnCy ViRuS AnD oTHER HumAn RETRoViRuSES (a reverse transcriptase) that directs the synthesis of a DNA form of the viral genome after infection of a host cell. The designation retrovirus denotes that information in the form of RNA is transcribed into DNA in the host cell—a sequence that overturned a central dogma of molecular biology: that information passes unidirectionally from DNA to RNA to protein. The observation that RNA was the source of genetic information in the causative agents of certain animal tumors led to a number of paradigm-shifting biologic insights regarding not only the direction of genetic information passage but also the viral etiology of certain cancers and the concept of oncogenes as normal host genes scavenged and altered by a viral vector.


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InternalMed_Harrison. The family Retroviridae includes seven subfamilies (Table 225e-1). Members of two of the families infect humans with pathologic consequences: the deltaretroviruses, of which human T cell lymphotropic virus (HTLV) type 1 is the most important in humans; and lentiviruses, of which HIV is the most important in humans.


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InternalMed_Harrison. The wide variety of interactions of a retrovirus with its host range from completely benign events (e.g., silent carriage of endogenous retroviral sequences in the germline genome of many animal species) to rapidly fatal infections (e.g., exogenous infection with an oncogenic virus such as Rous sarcoma virus in chickens). The ability of retroviruses to acquire and alter the structure and function of host cell sequences has revolutionized our understanding of molecular carcinogenesis. The viruses can insert into the germline genome of the host cell and behave as a transposable or movable genetic element. They can activate or inactivate genes near the site of integration into the genome. They can rapidly alter their own genome by recombination and mutation under selective environmental stimuli.


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InternalMed_Harrison. Most human viral diseases occur as a consequence of tissue destruction either directly by the virus itself or indirectly by the host’s response to the virus. Although these mechanisms are operative in retroviral infections, retroviruses have additional mechanisms of inducing disease, including the malignant transformation of an infected cell and the induction of an immunodeficiency state that renders the host susceptible to opportunistic diseases (infections and neoplasms; Chap. 226). a polyadenylation site at the 3′ end, which influences mRNA turnover (i.e., messages with shorter polyA tails turn over faster than messages with longer polyA tails). However, the retroviral RNA is not translated; instead it is transcribed into DNA. The DNA form of the retroviral genome is called a provirus.


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InternalMed_Harrison. The replication cycle of retroviruses proceeds in two phases (Fig. 225e-1). In the first phase, the virus enters the cytoplasm after binding to one or more specific cell-surface receptors; the viral RNA and reverse transcriptase synthesize a double-strand DNA version of the RNA template; and the provirus moves into the nucleus and integrates into the host cell genome. This proviral integration is permanent. Although some animal retroviruses integrate into a single specific site of the host genome in every infected cell, the human retroviruses integrate randomly. This first phase of replication depends entirely on gene products in the virus. The second phase includes the synthesis and processing of viral genomes, mRNAs, and proteins using host cell machinery, often under the influence of viral gene products. Virions are assembled and released from the cell by budding from the membrane; host cell membrane proteins are frequently incorporated into the envelope of the virus. Proviral


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InternalMed_Harrison. of viral gene products. Virions are assembled and released from the cell by budding from the membrane; host cell membrane proteins are frequently incorporated into the envelope of the virus. Proviral integration occurs during the S-phase of the cell cycle; thus, in general, nondividing cells are resistant to retroviral infection. Only the lentiviruses are able to infect nondividing cells. Once a host cell is infected, it is infected for the life of the cell. Retroviral genomes include both coding and noncoding sequences (Fig. 225e-2). In general, noncoding sequences are important recognition signals for DNA or RNA synthesis or processing events and are located in the 5′ and 3′ terminal regions of the genome. All retroviral genomes are terminally redundant, containing identical sequences called long terminal repeats (LTRs). The ends of the retroviral RNA genome differ slightly in sequence from the integrated retroviral DNA. In the latter, the LTR sequences are repeated in both the 5′


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InternalMed_Harrison. called long terminal repeats (LTRs). The ends of the retroviral RNA genome differ slightly in sequence from the integrated retroviral DNA. In the latter, the LTR sequences are repeated in both the 5′ and the 3′ terminus of the virus. The LTRs contain sequences involved in initiating the expression of the viral proteins, the integration of the provirus, and the polyadenylation of viral RNAs. The primer binding site, which is critical for the initiation of reverse transcription, and the viral packaging sequences are located outside the LTR sequences. The coding regions include the gag (group-specific antigen, core protein), pol (RNA-dependent DNA polymerase), and env (envelope) genes. The gag gene encodes a precursor polyprotein that is cleaved to form three to five capsid proteins; a fraction of the Gag precursor proteins also contain a protease responsible for cleaving the Gag and Pol polyproteins. A Gag-Pol polyprotein gives rise to the protease that is responsible for cleaving the


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InternalMed_Harrison. of the Gag precursor proteins also contain a protease responsible for cleaving the Gag and Pol polyproteins. A Gag-Pol polyprotein gives rise to the protease that is responsible for cleaving the Gag-Pol polyprotein. The pol gene encodes three proteins: the reverse transcriptase, the integrase, and the protease. The reverse transcriptase copies the viral RNA into the double-strand DNA provirus, which inserts itself into the host cell DNA via the action of integrase. The protease cleaves the Gag-Pol polyprotein into smaller protein products. The env gene encodes the envelope glycoproteins: one protein that binds to specific surface receptors and determines what cell types can be infected and a smaller transmembrane protein that anchors the complex to the envelope. Fig. 225e-3 shows how the retroviral gene products make up the virus structure.


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InternalMed_Harrison. CHAPTER 225e The Human Retroviruses Adsorption to specific receptor


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InternalMed_Harrison. FIgURE 225e-1 The life cycle of retroviruses. A. Overview of virus replication. The retrovirus enters a target cell by binding to a specific cell-surface receptor; once the virus is internalized, its RNA is released from the nucleocapsid and is reverse-transcribed into proviral DNA. The provirus is inserted into the genome and then transcribed into RNA; the RNA is translated; and virions assemble and are extruded from the cell membrane by budding. B. Overview of retroviral gene expression. The provirus is transcribed, capped, and polyadenylated. Viral RNA molecules then have one of three fates: they are exported to the cytoplasm, where they are packaged as the viral RNA in infectious viral particles; they are spliced to form the message for the envelope polyprotein; or they are translated into Gag and Pol proteins. Most of the messages for the Pol protein fail to initiate Pol translation because of a stop codon before its initiation; however, in a fraction of the messages, the stop


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InternalMed_Harrison. into Gag and Pol proteins. Most of the messages for the Pol protein fail to initiate Pol translation because of a stop codon before its initiation; however, in a fraction of the messages, the stop codon is missed and the Pol proteins are translated.


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InternalMed_Harrison. (Modified from JM Coffin, in BN Fields, DM Knipe [eds]: Fields Virology. New York, Raven, 1990; with permission.)


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InternalMed_Harrison. HTLVs have a region between env and the 3′ LTR that encodes several proteins and transcripts in overlapping reading frames (Fig. 225e-2). Tax is a 40-kDa protein that does not bind to DNA but induces the expression of host cell transcription factors that alter host cell gene expression and is capable of inducing cell transformation under certain circumstances. Rex is a 27-kDa protein that regulates the expression of viral mRNAs. Other transcripts from this region (p12, p13, p30) tend to restrict expression of viral genes and diminish the immunogenicity of infected cells. The protein of HBZ, a product of the complementary proviral DNA strand, interacts with many cellular transcription factors and signaling proteins. It stimulates proliferation of infected cells and is the only viral product universally expressed in HTLV-1-infected tumor cells. These proteins are produced from messages that are similar but that are spliced differently from overlapping but distinct exons.


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InternalMed_Harrison. The lentiviruses in general, and HIV-1 and -2 in particular, contain a larger genome than other pathogenic retroviruses. They contain an untranslated region between pol and env that encodes portions of several proteins, varying with the reading frame into which the mRNA is spliced. Tat is a 14-kDa protein that augments the expression of virus from the LTR. The Rev protein of HIV-1, similar to the Rex protein of HTLV, regulates RNA splicing and/or RNA transport. The Nef protein downregulates CD4, the cellular receptor for HIV; alters host T cell–activation pathways; and enhances viral infectivity. The Vif protein is necessary for the proper assembly of the HIV nucleoprotein core in many types of cells; without Vif, proviral DNA is not efficiently produced in these infected cells. In addition, the Vif protein targets APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide, a cytidine deaminase that mutates the viral sequence) for proteasomal degradation, thus blocking its


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InternalMed_Harrison. the Vif protein targets APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide, a cytidine deaminase that mutates the viral sequence) for proteasomal degradation, thus blocking its virus-suppressing effect. Vpr, Vpu (HIV-1 only), and Vpx (HIV-2 only) are viral proteins encoded by translation of the same message in different reading frames. As noted above, oncogenic retroviruses depend on cell proliferation for their replication; lentiviruses can infect nondividing cells, largely through effects mediated by Vpr. Vpr facilitates transport of the provirus into the nucleus and can induce other cellular changes, such as G2 growth arrest and differentiation of some target cells. Vpx is structurally related to Vpr, but its functions are not fully defined. Vpu promotes the degradation of CD4 in the endoplasmic reticulum and stimulates the release of virions from infected cells.


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InternalMed_Harrison. Retroviruses can be either exogenously acquired (by infection with an infected cell or a free virion capable of replication) or transmitted in the germline as endogenous virus. Endogenous retroviruses are often replication defective. The human genome contains endogenous retroviral sequences, but there are no known replication-competent endogenous retroviruses in humans.


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InternalMed_Harrison. In general, viruses that contain only the gag, pol, and env genes either are not pathogenic or take a long time to induce disease; these observations indicate the importance of the other regulatory genes in viral disease pathogenesis. The pathogenesis of neoplastic transformation by retroviruses relies on the chance integration of the provirus at a spot in the genome resulting in the expression of a cellular gene (protooncogene) that becomes transforming by virtue of its unregulated expression. For example, avian leukosis virus causes B cell leukemia by inducing the expression of myc. Some retroviruses possess captured and altered cellular genes near their integration site, and these viral oncogenes can transform the infected host cell. Viruses that have oncogenes often have lost a portion of their genome that is required for replication. Such viruses need helper viruses to reproduce, a feature that may explain why these acute transforming retroviruses are rare in nature. All human


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InternalMed_Harrison. of their genome that is required for replication. Such viruses need helper viruses to reproduce, a feature that may explain why these acute transforming retroviruses are rare in nature. All human retroviruses identified to date are exogenous and are not acutely transforming (i.e., they lack a transforming oncogene).


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InternalMed_Harrison. These remarkable properties of retroviruses have led to experimental efforts to use them as vectors to insert specific genes into particular cell types, a process known as gene therapy or gene transfer. The process could be used to repair a genetic defect or to introduce a new property that could be used therapeutically; for example, a gene (e.g., thymidine kinase) that would make a tumor cell susceptible to killing by a drug (e.g., ganciclovir) could be inserted. One source of concern about the use of retroviral vectors in humans is that replication-competent viruses might rescue endogenous retroviral replication, with unpredictable results. This concern is not merely hypothetical: the detection of proteins encoded by endogenous retroviral sequences on the surface of cancer cells implies that the genetic events leading to the cancer were able to activate the synthesis of these usually silent genes.


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InternalMed_Harrison. HTLV-1 was isolated in 1980 from a T cell lymphoma cell line from a patient originally thought to have cutaneous T cell lymphoma. Later it became clear that the patient had a distinct form of lymphoma (originally reported in Japan) called adult T cell leukemia/lymphoma (ATL). Serologic data have determined that HTLV-1 is the cause of at least two important diseases: ATL and tropical spastic paraparesis, also LTR GAG POL LTR LTR MA CA NC PR RT GP46 p21HTLV-I,II TAX, p40 REX, p27 p30 TAT, p14 PR POL REV, p19


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InternalMed_Harrison. FIgURE 225e-2 Genomic structure of retroviruses. The murine leukemia virus MuLV has the typical three structural genes: gag, pol, and env. The gag region gives rise to three proteins: matrix (MA), capsid (CA), and nucleic acid–binding (NC) proteins. The pol region encodes both a protease (PR) responsible for cleaving the viral polyproteins and a reverse transcriptase (RT ). In addition, HIV pol encodes an integrase (IN). The env region encodes a surface protein (SU) and a small transmembrane protein ( TM). The human retroviruses have additional gene products translated in each of the three possible reading frames. HTLV-1 and HTLV-2 have tax and rex genes with exons on either side of the env gene. HIV-1 and HIV-2 have six accessory gene products: tat, rev, vif, nef, vpr, and either vpu (in HIV-1) or vpx (in HIV-2). The genes for these proteins are located mainly between the pol and env genes. GP, glycoprotein; HBZ, HTLV-1 basic leucine zipper domain–containing protein; LTR, long termi


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InternalMed_Harrison. HIV-1) or vpx (in HIV-2). The genes for these proteins are located mainly between the pol and env genes. GP, glycoprotein; HBZ, HTLV-1 basic leucine zipper domain–containing protein; LTR, long termi nal repeat.


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InternalMed_Harrison. called HTLV-1-associated myelopathy (HAM). HTLV-1 may also play a role in infective dermatitis, arthritis, uveitis, and Sjögren’s syndrome. Two years after the isolation of HTLV-1, HTLV-2 was isolated from a patient with an unusual form of hairy cell leukemia that affected


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InternalMed_Harrison. Two years after the isolation of HTLV-1, HTLV-2 was isolated from a patient with an unusual form of hairy cell leukemia that affected FIgURE 225e-3 Schematic structure of human retroviruses. The surface glycoprotein (SU) is responsible for binding to receptors of host cells. The transmembrane protein (TM) anchors SU to the virus. NC is a nucleic acid–binding protein found in association with the viral RNA. A protease (PR) cleaves the polyproteins encoded by the gag, pol, and env genes into their functional components. RT is reverse transcriptase, and IN is an integrase present in some retroviruses (e.g., HIV-1) that facilitates insertion of the provirus into the host genome. The matrix protein (MA) is a Gag protein closely associated with the lipid of the envelope. The capsid protein (CA) forms the major internal structure of the virus, the core shell.


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InternalMed_Harrison. T cells. Epidemiologic studies of HTLV-2 failed to reveal a consistent disease association. Similarly, HTLV-3 and HTLV-4 have been identified but have no known disease association. Because the biology of HTLV-1 and that of HTLV-2 are similar, the following discussion will focus on HTLV-1.


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InternalMed_Harrison. Human glucose transporter protein 1 (GLUT-1) functions as a receptor for HTLV-1, probably acting together with neuropilin-1 (NRP1) and heparan sulfate proteoglycans. Generally, only T cells are productively infected, but infection of B cells and other cell types is occasionally detected. The most common outcome of HTLV-1 infection is latent carriage of randomly integrated provirus in CD4+ T cells. HTLV-1 does not contain an oncogene and does not insert into a unique site in the genome. Indeed, most infected cells express no viral gene products. The only viral gene product that is routinely expressed in tumor cells transformed by HTLV-1 in vivo is hbz. The tax gene is thought to be critical to the transformation process but is not expressed in the tumor cells of many ATL patients, possibly because of the immunogenicity of tax-expressing cells. Cells transformed in vitro, by contrast, actively transcribe HTLV-1 RNA and produce infectious virions. Most HTLV-1-transformed cell lines are


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InternalMed_Harrison. because of the immunogenicity of tax-expressing cells. Cells transformed in vitro, by contrast, actively transcribe HTLV-1 RNA and produce infectious virions. Most HTLV-1-transformed cell lines are the result of the infection of a normal host T cell in vitro. It is difficult to establish cell lines derived from authentic ATL cells.


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InternalMed_Harrison. Although tax does not itself bind to DNA, it does induce the expression of a wide range of host cell gene products, including transcription factors (especially c-rel/NF-κB, ets-1 and -2, and members of the fos/jun family), cytokines (e.g., interleukin [IL] 2, granulocytemacrophage colony-stimulating factor, and tumor necrosis factor), membrane proteins and receptors (major histocompatibility [MHC] molecules and IL-2 receptor α), and chromatin remodeling complexes. The genes activated by tax are generally controlled by transcription factors of the c-rel/NF-κB and cyclic AMP response element binding (CREB) protein families. It is unclear how this induction of host


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InternalMed_Harrison. CHAPTER225e The Human Retroviruses 225e-4 gene expression leads to neoplastic transformation; tax can interfere with G1 and mitotic cell-cycle checkpoints, block apoptosis, inhibit DNA repair, and promote antigen-independent T cell proliferation. Induction of a cytokine–autocrine loop has been proposed; however, IL-2 is not the crucial cytokine. The involvement of IL-4, IL-7, and IL-15 has been proposed. In light of the irregular expression of tax in ATL cells, it has been suggested that tax is important in the early phases of transformation but is not essential for the maintenance of the transformed state. The maintenance role is thought to be due to hbz expression. As is clear from the epidemiology of HTLV-1 infection, transformation of an infected cell is a rare event and may depend on heterogeneous second, third, or fourth genetic hits. No consistent chromosomal abnormalities have been described in ATL; however, aneuploidy is common and individual cases with p53 mutations and


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InternalMed_Harrison. on heterogeneous second, third, or fourth genetic hits. No consistent chromosomal abnormalities have been described in ATL; however, aneuploidy is common and individual cases with p53 mutations and translocations involving the T cell receptor genes on chromosome 14 have been reported. Tax may repress certain DNA repair enzymes, permitting the accumulation of genetic damage that would normally be repaired. However, the molecular pathogenesis of HTLV-1-induced neoplasia is not fully understood.


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InternalMed_Harrison. FEATURES OF HTLV-1 INFECTION Epidemiology HTLV-1 infection is transmitted in at least three ways: from mother to child, especially via breast milk; through sexual activity, more commonly from men to women; and through the blood—via contaminated transfusions or contaminated needles. The virus is most commonly transmitted perinatally. Compared with HIV, which can be transmitted in cell-free form, HTLV-1 is less infectious, and its transmission usually requires cell-to-cell contact.


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InternalMed_Harrison. HTLV-1 is endemic in southwestern Japan and Okinawa, where >1 million persons are infected. Antibodies to HTLV-1 are present in the serum of up to 35% of Okinawans, 10% of residents of the Japanese island of Kyushu, and <1% of persons in nonendemic regions of Japan. Despite this high prevalence of infection, only ~500 cases of ATL are diagnosed in this area each year. Clusters of infection have been noted in other areas of the Orient, such as Taiwan; in the Caribbean basin, including northeastern South America; in northwestern South America; in central and southern Africa; in Italy, Israel, Iran, and Papua New Guinea; in the Arctic; and in the southeastern part of the United States (Fig. 225e-4). An estimated 5–10 million persons have HTLV-1 infection worldwide.


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InternalMed_Harrison. Progressive spastic or ataxic myelopathy developing in an individual who is HTLV-1 positive (i.e., who has serum antibodies to HTLV-1) may be due to direct infection of the nervous system with the virus, but destruction of the pyramidal tracts appears to involve HTLV-1-infected CD4+ T cells; a similar disorder may result from infection with HIV or HTLV-2. In rare instances, patients with HAM are seronegative but have detectable antibody to HTLV-1 in cerebrospinal fluid (CSF).


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InternalMed_Harrison. The cumulative lifetime risk of developing ATL is 3% among HTLV-1-infected patients, with a threefold greater risk among men than among women; a similar cumulative risk is projected for HAM (4%), but with women more commonly affected than men. The distribution of these two diseases overlaps the distribution of HTLV-1, with >95% of affected patients showing serologic evidence of HTLV-1 infection. The latency period between infection and the emergence of disease is 20–30 years for ATL. For HAM, the median latency period is ~3.3 years (range, 4 months to 30 years). The development of ATL is rare among persons infected by blood products; however, ~20% of patients with HAM acquire HTLV-1 from contaminated blood. ATL is more common among perinatally infected individuals, whereas HAM is more common among persons infected via sexual transmission.


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InternalMed_Harrison. Associated Diseases • ATL Four clinical types of HTLV-1-induced neoplasia have been described: acute, lymphomatous, chronic, and smoldering. All of these tumors are monoclonal proliferations of CD4+ postthymic T cells with clonal proviral integrations and clonal T cell receptor gene rearrangements.


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InternalMed_Harrison. AcuTe ATL About 60% of patients who develop malignancy have classic acute ATL, which is characterized by a short clinical prodrome (~2 weeks between the first symptoms and the diagnosis) and an aggressive natural history (median survival period, 6 months). The clinical picture is dominated by rapidly progressive skin lesions, pulmonary involvement, hypercalcemia, and lymphocytosis with cells containing lobulated or “flower-shaped” nuclei (see Fig. 134-10). The malignant cells have monoclonal proviral integrations and express CD4, CD3, and CD25 (low-affinity IL-2 receptors) on their surface. Serum levels of CD25 can be used as a tumor marker. Anemia and thrombocytopenia are rare. The skin lesions may be difficult to distinguish from those in mycosis fungoides. Lytic bone lesions, which are common, do not contain tumor cells but rather are composed of osteolytic cells, usually without osteoblastic activity. Despite the leukemic picture, bone marrow involvement is patchy in most cases.


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InternalMed_Harrison. The hypercalcemia of ATL is multifactorial; the tumor cells produce osteoclast-activating factors (tumor necrosis factor α, IL-1, lymphotoxin) and can also produce a parathyroid hormone–like molecule. Affected patients have an underlying immunodeficiency that makes them susceptible to opportunistic infections similar to those seen in patients with AIDS (Chap. 226). The pathogenesis of the immunodeficiency is unclear. Pulmonary infiltrates in ATL patients reflect leukemic infiltration half the time and opportunistic infections with organisms such as Pneumocystis and other fungi the other half. Gastrointestinal symptoms are nearly always related to opportunistic infection. Strongyloides stercoralis is a gastrointestinal parasite that has a pattern of endemic distribution similar to that of HTLV-1. HTLV-1-infected persons also infected with this parasite may develop ATL more often or more rapidly than those without Strongyloides infections. Serum concentrations of lactate dehydrogenase


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InternalMed_Harrison. HTLV-1. HTLV-1-infected persons also infected with this parasite may develop ATL more often or more rapidly than those without Strongyloides infections. Serum concentrations of lactate dehydrogenase and alkaline


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InternalMed_Harrison. FIgURE 225e-4 Global distribution of HTLV-1 infection. Countries with a prevalence of HTLV-1 infection of 1–5% are shaded darkly. Note that the distribution of infected patients is not uniform in endemic countries. For example, the people of southwestern Japan and northeastern Brazil are more commonly affected than those in other regions of those countries. phosphatase are often elevated in ATL. About 10% of patients have leptomeningeal involvement leading to weakness, altered mental status, paresthesia, and/or headache. Unlike other forms of central nervous system (CNS) lymphoma, ATL may be accompanied by normal CSF protein levels. The diagnosis depends on finding ATL cells in the CSF (Chap. 134).


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InternalMed_Harrison. LymphomATous ATL The lymphomatous type of ATL occurs in ~20% of patients and is similar to the acute form in its natural history and clinical course, except that circulating abnormal cells are rare and lymphadenopathy is evident. The histology of the lymphoma is variable but does not influence the natural history. In general, the diagnosis is suspected on the basis of the patient’s birthplace (see “Epidemiology,” above) and the presence of skin lesions and hypercalcemia. The diagnosis is confirmed by the detection of antibodies to HTLV-1 in serum. chronic ATL Patients with the chronic form of ATL generally have normal serum levels of calcium and lactate dehydrogenase and no involvement of the CNS, bone, or gastrointestinal tract. The median duration of survival for these patients is 2 years. In some cases, chronic ATL progresses to the acute form of the disease.


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InternalMed_Harrison. smoLdering ATL Fewer than 5% of patients have the smoldering form of ATL. In this form, the malignant cells have monoclonal proviral integration; <5% of peripheral blood cells exhibit typical morphologic abnormalities; hypercalcemia, adenopathy, and hepatosplenomegaly do not develop; the CNS, the bones, and the gastrointestinal tract are not involved; and skin lesions and pulmonary lesions may be present. The median survival period for this small subset of patients appears to be ≥5 years.


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InternalMed_Harrison. hAm (TropicAL spAsTic pArApAresis) In contrast to ATL, in which there is a slight predominance of male patients, HAM affects female patients disproportionately. HAM resembles multiple sclerosis in certain ways (Chap. 458). The onset is insidious. Symptoms include weakness or stiffness in one or both legs, back pain, and urinary incontinence. Sensory changes are usually mild, but peripheral neuropathy may develop. The disease generally takes the form of slowly progressive and unremitting thoracic myelopathy; one-third of patients are bedridden within 10 years of diagnosis, and one-half are unable to walk unassisted by this point. Patients display spastic paraparesis or paraplegia with hyperreflexia, ankle clonus, and extensor plantar responses. Cognitive function is usually spared; cranial nerve abnormalities are unusual.


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InternalMed_Harrison. Magnetic resonance imaging (MRI) reveals lesions in both the white matter and the paraventricular regions of the brain as well as in the spinal cord. Pathologic examination of the spinal cord shows symmetric degeneration of the lateral columns, including the corticospinal tracts; some cases involve the posterior columns as well. The spinal meninges and cord parenchyma contain an inflammatory infiltrate with myelin destruction.


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InternalMed_Harrison. HTLV-1 is not usually found in cells of the CNS but may be detected in a small population of lymphocytes present in the CSF. In general, HTLV-1 replication is greater in HAM than in ATL, and patients with HAM have a stronger immune response to the virus. Antibodies to HTLV-1 are present in the serum and appear to be produced in the CSF of HAM patients, where titers are often higher than in the serum. The pathophysiology of HAM may involve the induction of autoimmune destruction of neural cells by T cells with specificity for viral components such as Tax or Env proteins. One theory is that susceptibility to HAM may be related to the presence of human leukocyte antigen (HLA) alleles capable of presenting viral antigens in a fashion that leads to autoimmunity. Insufficient data are available to confirm an HLA association. However, antibodies in the sera of HAM patients have been shown to bind a neuron-specific antigen (heteronuclear ribonuclear protein A1 [hnRNP A1]) and to interfere


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InternalMed_Harrison. to confirm an HLA association. However, antibodies in the sera of HAM patients have been shown to bind a neuron-specific antigen (heteronuclear ribonuclear protein A1 [hnRNP A1]) and to interfere with neurotransmission in vitro.


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InternalMed_Harrison. It is unclear what factors influence whether HTLV-1 infection will cause disease and, if it does, whether it will induce a neoplasm (ATL) or an autoimmune disorder (HAM). Differences in viral strains, the susceptibility of particular MHC haplotypes, the route of HTLV-1 infection, the viral load, and the nature of the HTLV-1-related immune 225e-5 response are putative factors, but few definitive data are available. oTher puTATive hTLv-1-reLATed diseAses Even in the absence of the full clinical picture of HAM, bladder dysfunction is common in HTLV-1-infected women. In areas where HTLV-1 is endemic, diverse inflammatory and autoimmune diseases have been attributed to the virus, including uveitis, dermatitis, pneumonitis, rheumatoid arthritis, and polymyositis. However, a causal relationship between HTLV-1 and these illnesses has not been established.


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InternalMed_Harrison. Prevention Women in endemic areas should not breast-feed their children, and blood donors should be screened for serum antibodies to HTLV-1. As in the prevention of HIV infection, the practice of safe sex and the avoidance of needle sharing are important.


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InternalMed_Harrison. For the small number of patients who develop HTLV-1-related disease, therapies are not curative. In patients with the acute and lymphomatous types of ATL, the disease progresses rapidly. Hypercalcemia is generally controlled by glucocorticoid administration and cytotoxic therapy directed against the neoplasm. The tumor is highly responsive to combination chemotherapy that is used against other forms of lymphoma; however, patients are susceptible to overwhelming bacterial and opportunistic infections, and ATL relapses within 4–10 months after remission in most cases. The combination of interferon α and zidovudine may extend survival. Because viral replication is not clearly associated with ATL progression, zidovudine is probably effective through its cytotoxic effects (as a chain-terminating thymidine analogue) rather than its antiviral effects. LSG15, a multidrug chemotherapy program developed in Japan, induces complete responses in about one-third of patients, about half of whom


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InternalMed_Harrison. thymidine analogue) rather than its antiviral effects. LSG15, a multidrug chemotherapy program developed in Japan, induces complete responses in about one-third of patients, about half of whom survive more than 2 years; however, but the median survival time is about 13 months. A pilot trial suggested that mogamulizumab, an antibody to CCR4 (a receptor for a number of chemokines, including RANTES and TARC), improved response rates when added to chemotherapy. An experimental approach using an yttrium 90–labeled or toxin-conjugated antibody to the IL-2 receptor appears promising but is not widely available. Patients with the chronic or smoldering form of ATL may be managed with an expectant approach: treat any infections, and watch and wait for signs of progression to acute disease.


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InternalMed_Harrison. Patients with HAM may obtain some benefit from the use of glucocorticoids to reduce inflammation. Antiretroviral regimens have not been effective. In one study, danazol (200 mg three times daily) produced significant neurologic improvement in five of six treated patients, with resolution of urinary incontinence in two cases, decreased spasticity in three, and restoration of the ability to walk after confinement to a wheelchair in two. Antibody to IL-15 receptor β chain has been tested with some promising clinical effects in small numbers of patients. Physical therapy and rehabilitation are important components of management. CHAPTER 225e The Human Retroviruses Epidemiology HTLV-2 is endemic in certain Native American tribes and in Africa. It is generally considered to be a New


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InternalMed_Harrison. CHAPTER 225e The Human Retroviruses Epidemiology HTLV-2 is endemic in certain Native American tribes and in Africa. It is generally considered to be a New World virus that was brought from Asia to the Americas 10,000–40,000 years ago during the migration of infected populations across the Bering land bridge. The mode of transmission of HTLV-2 is probably the same as that of HTLV-1 (see above). HTLV-2 may be less readily transmitted sexually than HTLV-1.


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InternalMed_Harrison. Studies of large cohorts of injection drug users with serologic assays that reliably distinguish HTLV-1 from HTLV-2 indicated that the vast majority of HTLV-positive cohort members were infected with HTLV-2. The seroprevalence of HTLV in a cohort of 7841 injection drug users from drug treatment centers in Baltimore, Chicago, Los Angeles, New Jersey (Asbury Park and Trenton), New York City (Brooklyn and Harlem), Philadelphia, and San Antonio was 20.9%, with >97% of cases due to HTLV-2. The seroprevalence of HTLV-2 was higher in the Southwest and the Midwest than in the Northeast. In contrast, the seroprevalence of HIV-1 was higher in the Northeast than in the Southwest or the Midwest. Approximately 3% of the cohort members were infected with both HTLV-2 and HIV-1. The seroprevalence of HTLV-2 increased linearly with age. Women were significantly more likely to be infected with HTLV-2 than were men; the virus is thought to be more efficiently transmitted from male to female than from


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InternalMed_Harrison. increased linearly with age. Women were significantly more likely to be infected with HTLV-2 than were men; the virus is thought to be more efficiently transmitted from male to female than from female to male.


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InternalMed_Harrison. Associated Diseases Although HTLV-2 was isolated from a patient with a T cell variant of hairy cell leukemia, this virus has not been consistently associated with a particular disease and in fact has been thought of as “a virus searching for a disease.” However, evidence is accumulating that HTLV-2 may play a role in certain neurologic, hematologic, and dermatologic diseases. These data require confirmation, particularly in light of the previous confusion regarding the relative prevalences of HTLV-1 and HTLV-2 among injection drug users. Prevention Avoidance of needle sharing, adherence to safe-sex practices, screening of blood (by assays for HTLV-1, which also detect HTLV-2), and avoidance of breast-feeding by infected women are important principles in the prevention of spread of HTLV-2.


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InternalMed_Harrison. HIV-1 and HIV-2 are members of the lentivirus subfamily of Retroviridae and are the only lentiviruses known to infect humans. The lentiviruses are slow-acting by comparison with viruses that cause acute infection (e.g., influenza virus) but not by comparison with other retroviruses. The features of acute primary infection with HIV resemble those of more classic acute infections. The characteristic chronicity of HIV disease is consistent with the designation lentivirus. For a detailed discussion of HIV, see Chap. 226. Human Immunodeficiency virus disease: AIds and Related disorders Anthony S. Fauci, H. Clifford Lane AIDS was first recognized in the United States in the summer of 1981, 226 when the U.S. Centers for Disease Control and Prevention (CDC) reported the unexplained occurrence of Pneumocystis jiroveci (formerly P. carinii) pneumonia in five previously healthy homosexual men in Los Angeles and of Kaposi’s sarcoma (KS) with or without


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InternalMed_Harrison. P. jiroveci pneumonia and other opportunistic infections in 26 previously healthy homosexual men in New York, San Francisco, and Los Angeles. The disease was soon recognized in male and female injection drug users; in hemophiliacs and blood transfusion recipients; among female sexual partners of men with AIDS; and among infants born to mothers with AIDS. In 1983, human immunodeficiency virus (HIV) was isolated from a patient with lymphadenopathy, and by 1984 it was demonstrated clearly to be the causative agent of AIDS. In 1985, a sensitive enzyme-linked immunosorbent assay (ELISA) was developed; this led to an appreciation of the scope and evolution of the HIV epidemic at first in the United States and other developed nations and ultimately among developing nations throughout the world (see “HIV Infection and AIDS Worldwide,” below). The staggering worldwide evolution of the HIV pandemic has been matched by an explosion of information in the areas of HIV virology, pathogenesis (both


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InternalMed_Harrison. “HIV Infection and AIDS Worldwide,” below). The staggering worldwide evolution of the HIV pandemic has been matched by an explosion of information in the areas of HIV virology, pathogenesis (both immunologic and virologic), treatment of HIV disease, treatment and prophylaxis of the opportunistic diseases associated with HIV infection, and prevention of HIV infection. The information flow related to HIV disease is enormous and continues to expand, and it has become almost impossible for the health care generalist to stay abreast of the literature.


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InternalMed_Harrison. The purpose of this chapter is to present the most current information available on the scope of the epidemic; on its pathogenesis, treatment, and prevention; and on prospects for vaccine development. Above all, the aim is to provide a solid scientific basis and practical clinical guidelines for a state-of-the-art approach to the HIV-infected patient.


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InternalMed_Harrison. The current U.S. CDC classification system for HIV infection and AIDS categorizes people on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte measurement. A confirmed HIV case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within 6 months of the first HIV infection diagnosis, the stage is 0, and remains 0 until 6 months after diagnosis. Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been diagnosed (Table 226-1). Otherwise, the stage is determined by CD4 test results and immunologic criteria (Table 226-2). If none of these criteria apply (e.g., because of missing information on CD4 test results), the stage is U (unknown). The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than for the practical care of patients. Thus, the clinician should not focus


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InternalMed_Harrison. Bacterial infections, multiple or recurrenta Candidiasis of bronchi, trachea, or lungs Candidiasis of esophagus Cervical cancer, invasiveb Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month Cytomegalovirus retinitis (with loss of vision) Encephalopathy attributed to HIV Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis, pneumo nitis, or esophagitis (onset at age >1 month) Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or Mycobacterium kansasii, disseminated or


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InternalMed_Harrison. Mycobacterium tuberculosis of any site, pulmonary,b disseminated, or extrapulmonary Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia Pneumonia, recurrentb Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age >1 month Wasting syndrome attributed to HIV aOnly among children age <6 years. bOnly among adults, adolescents, and children age ≥6 years. Source: MMWR 63(No. RR-03), April 11, 2014.


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InternalMed_Harrison. Source: MMWR 63(No. RR-03), April 11, 2014. Human Immunodeficiency Virus Disease: AIDS and Related Disorders the transmembrane gp41. The HIV envelope exists as a trimeric heterodimer. The virion buds FIGuRE 226-1 A phylogenetic tree based on the complete genomes of primate immufrom the surface of the infected cell and incor-nodeficiency viruses. The scale (0.10) indicates a 10% difference at the nucleotide level. porates a variety of host proteins into its lipid (Prepared by Brian Foley, PhD, of the HIV Sequence Database, Theoretical Biology and Biophysics bilayer. The structure of HIV-1 is schematically Group, Los Alamos National Laboratory; additional information at www.hiv.lanl.gov/content/ diagrammed in Fig. 226-2B. sequence/HelpDocs/subtypes.html.)


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InternalMed_Harrison. Talapoin Dent’s DeBrazzas African green monkeys Red-capped mangabey Mandril-2 and drill Olive colobus Sun-tailed mandril-1 L’Hoest 0.10 Chimpanzee troglodytes HIV-2 and SIV from sooty mangabeys Mona, greater spot-nosed, and mustached monkeys Sykes Western red colobus HIV-1 O Group HIV-1 M Group HIV-1 N Group Chimpanzee troglodytes Chimpanzee schweinfurthii Gorilla HIV-1 P from chimpanzees and gorillas


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InternalMed_Harrison. FIGuRE 226-2 A. Electron micrograph of HIV. Figure illustrates a typical virion following budding from the surface of a CD4+ T lymphocyte, together with two additional incomplete virions in the process of budding from the cell membrane. B. Structure of HIV-1, including the gp120 envelope, gp41 transmembrane components of the envelope, genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid). (Copyright by George V. Kelvin.) (Adapted from RC Gallo: Sci Am 256:46, 1987.)C. Scanning electron micrograph of HIV-1 virions infecting a human CD4+ T lymphocyte. The original photograph was imaged at 8000× magnification. (Courtesy of Elizabeth R. Fischer, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases; with permission.) the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, resulting in the formation of double-stranded proviral


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InternalMed_Harrison. the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, resulting in the formation of double-stranded proviral HIVDNA. At the preintegration steps of the replication cycle, the viral genome is vulnerable to cellular factors that can block the progression of infection. In particular, the cytoplasmic tripartite motif-containing protein 5-α (TRIM5-α) is a host restriction factor that interacts with retroviral capsids (Fig. 226-3). Although the exact mechanisms of action of TRIM5-α remain unclear, the HIV-1 capsid is not recognized by the human form of TRIM5-α. Thus this host factor is not effective in restricting HIV-1 replication in human cells. The apolipoprotein B mRNA editing enzyme (catalytic polypeptide-like 3 [APOBEC3]) family of cellular proteins also inhibits progression of virus infection after virus has entered the cell and prior to entering the nucleus (Fig. 226-3). APOBEC3 proteins, which


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InternalMed_Harrison. 3 [APOBEC3]) family of cellular proteins also inhibits progression of virus infection after virus has entered the cell and prior to entering the nucleus (Fig. 226-3). APOBEC3 proteins, which are incorporated into virions and released into the cytoplasm of a newly infected cell, bind to the single minus-strand DNA intermediate and deaminate viral cytidine, causing hypermutation of retroviral genomes. HIV has evolved a powerful strategy to protect itself from APOBEC. The viral protein Vif targets APOBEC3 for proteasomal degradation.


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InternalMed_Harrison. With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase (Fig. 226-3). HIV provirus (DNA) integrates into the nuclear DNA preferentially within introns of active genes and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active production of virus.


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InternalMed_Harrison. Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease (see “Pathogenesis and Pathophysiology,” below). Following initial binding, fusion, and internalization of the nucleic acid contents of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell-surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that


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InternalMed_Harrison. regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristoylation, phosphorylation,


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InternalMed_Harrison. CHAPTER 226 Human Immunodeficiency Virus Disease: AIDS and Related Disorders Genomic RNA Reverse transcriptase Cellular DNA Unintegrated linear DNA Fusion Uncoating CD4 gp120 Protein synthesis, processing, and assembly Budding Release TetherinTRIM5APOBEC3GmRNA Integrated proviral DNA Genomic RNA Mature HIV virion HIV FIGuRE 226-3 The replication cycle of HIV. See text for description. (Adapted from AS Fauci: Nature 384:529, 1996.) and cleavage. The viral particle is formed by the assembly of HIV with virion detachment, although the HIV accessory protein Vpu proteins, enzymes, and genomic RNA at the plasma membrane of counteracts the effect through direct interactions with tetherin. the cells. Budding of the progeny virion through the lipid bilayer of During or soon after budding, the virally encoded protease catalyzes the host cell membrane is the point at which the core acquires its the cleavage of the gag-pol precursor to yield the mature virion.


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InternalMed_Harrison. external envelope and where the host restriction factor tetherin can Progression through the virus replication cycle is profoundly influ inhibit the release of budding particles (Fig. 226-3). Tetherin is an enced by a variety of viral regulatory gene products. Likewise, each interferon (IFN)-induced type II transmembrane protein that interferes point in the replication cycle of HIV is a real or potential target for therapeutic intervention. Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proved clinically to be susceptible to pharmacologic disruption.


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InternalMed_Harrison. Figure 226-5 illustrates schematically the arrangement of the HIV genome. Like other retroviruses, HIV-1 has genes that encode the structural proteins of the virus: gag encodes the proteins that form the core of the virion (including p24 antigen); pol encodes the enzymes responsible for protease processing of viral proteins, reverse transcription, and integration; and env encodes the envelope glycoproteins. However, HIV-1 is more complex than other retroviruses, particularly those of the nonprimate group, in that it also contains at least six other FIGuRE 226-4 Binding and fusion of HIV-1 with its target cell. HIV-1 binds to its target genes (tat, rev, nef, vif, vpr, and vpu), which code for cell via the CD4 molecule, leading to a conformational change in the gp120 molecule proteins involved in the modification of the host that allows it to bind to the co-receptor CCR5 (for R5-using viruses). The virus then firmly cell to enhance virus growth and the regulation of attaches to the host


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InternalMed_Harrison. in the modification of the host that allows it to bind to the co-receptor CCR5 (for R5-using viruses). The virus then firmly cell to enhance virus growth and the regulation of attaches to the host cell membrane in a coiled-spring fashion via the newly exposed viral gene expression. Several of these proteins are gp41 molecule. Virus-cell fusion occurs as the transitional intermediate of gp41 under-thought to play a role in the pathogenesis of HIV goes further changes to form a hairpin structure that draws the two membranes into disease; their various functions are listed in Fig. close proximity (see text for details). (Adapted from D Montefiori, JP Moore: Science 283:336, 226-5. Flanking these genes are the long terminal 1999; with permission.) repeats (LTRs), which contain regulatory elements


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InternalMed_Harrison. LTR Long terminal repeat Contains control regions that bind host transcription factors (NF-˜B, NFAT, Sp.1, TBP) Required for the initiation of transcription Contains RNA trans-acting response element (TAR) that binds Tat vifViral infectivity factor (p23) Overcomes inhibitory effects of APOBEC3, preventing hypermutation and viral DNA degradation vpuViral protein U Promotes CD4 degradation and influences virion release Overcomes inhibitory effects of tetherin envgp160 envelope protein Cleaved in endoplasmic reticulum to gp120 (SU) and gp41 (TM) gp120 mediates CD4 and chemokine receptor binding, while gp41 mediates fusion Contains RNA response element (RRE) that binds Rev gagPr55gag Polyprotein processed by PR MA, matrix (p17) Undergoes myristylation that helps target gag polyprotein to lipid rafts CA capsid (p24) polPolymerase Encodes a variety of viral enzymes, including PR (p10), RT and RNAase H (p66/51), and IN (p32) all processed by PR vprViral protein R (p15) Promotes G2 cell-cycle


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InternalMed_Harrison. rafts CA capsid (p24) polPolymerase Encodes a variety of viral enzymes, including PR (p10), RT and RNAase H (p66/51), and IN (p32) all processed by PR vprViral protein R (p15) Promotes G2 cell-cycle arrest Facilitates HIV infection of macrophages revRegulator of viral gene expression (p19) Binds RRE Inhibits viral RNA splicing and promotes nuclear export of incompletely spliced viral RNAs 5˛U3 RU5 U3 RU5


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InternalMed_Harrison. Binds cyclophilin A and CPSF6 Target of TRIM5° NC, nucleocapsid (p7) Zn finger, RNA-binding protein p6 Regulates the terminal steps in virion budding through interactions with TSG101 and ALIX1 Promotes down regulation of surface CD4 and MHC 1 expression Alters state of cellular activation Progression to disease slowed significantly in absence of Nef In presence of host cyclin T1 and CDK9 enhances RNA Pol II elongation on the viral DNA template FIGuRE 226-5 Organization of the genome of the HIV provirus together with a summary description of its 9 genes encoding 15 proteins. (Adapted from WC Greene, BM Peterlin: Nat Med 8:673, 2002.) involved in gene expression (Fig. 226-5). The major difference between the genomes of HIV-1 and HIV-2 is the fact that HIV-2 lacks the vpu gene and has a vpx gene not contained in HIV-1.


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InternalMed_Harrison. Molecular analyses of HIV isolates reveal varying levels of sequence diversity over all regions of the viral genome. For example, the degree of difference in the coding sequences of the viral envelope protein ranges from a few percent (very close, among isolates from the same infected individual) to more than 50% (extreme diversity, between isolates from the different groups of HIV 1: M, N, O, and P). The changes tend to cluster in hypervariable regions. HIV can evolve by several means, including simple base substitution, insertions and deletions, recombination, and gain and loss of glycosylation sites. HIV sequence diversity arises directly from the limited fidelity of the reverse transcriptase. The balance of immune pressure and functional constraints on proteins influences the regional level of variation within proteins. For example, Envelope, which is exposed on the surface of the virion and is under immune selective pressure from both antibodies and cytolytic T lymphocytes, is


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InternalMed_Harrison. level of variation within proteins. For example, Envelope, which is exposed on the surface of the virion and is under immune selective pressure from both antibodies and cytolytic T lymphocytes, is extremely variable, with clusters of mutations in hypervariable domains. In contrast, reverse transcriptase, with important enzymatic functions, is relatively conserved, particularly around the active site. The extraordinary variability of HIV-1 contrasts markedly with the relative stability of HTLV-1 and -2.


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InternalMed_Harrison. The four groups (M, N, O and P) of HIV-1 are the result of four separate chimpanzee-to-human (or possibly gorilla-to-human for groups O and P) transfers. Group M (major), which is responsible for most of the infections in the world, has diversified into subtypes and intersubtype recombinant forms, due to “sub-epidemics” within humans after one of those transfers.


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InternalMed_Harrison. Among primate lentiviruses, HIV-1 is most closely related to viruses isolated from chimpanzees and gorillas (Fig. 226-1). The chimpanzee subspecies Pan troglodytes troglodytes has been established to be the natural reservoir of the HIV-1 M and N groups. The rare viruses of the HIV-1 O and P groups are most closely related to viruses found in Cameroonian gorillas. The M group comprises nine subtypes, or clades, designated A, B, C, D, F, G, H, J, and K, as well as more than 60 known circulating recombinant forms (CRFs) and numerous unique recombinant forms. Intersubtype recombinants are generated by infection of an individual with two subtypes that then recombine and create a virus with a selective advantage. These CRFs range from highly prevalent forms such as CRF01_AE, common in southeast Asia, and CRF02_AG from west and central Africa, to a large number of CRFs that are relatively rare, either because they are of a more recent origin (newly recombined) or because they have not broken


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InternalMed_Harrison. Asia, and CRF02_AG from west and central Africa, to a large number of CRFs that are relatively rare, either because they are of a more recent origin (newly recombined) or because they have not broken out into a major population. The subtypes and CRFs create the major lineages of the M group of HIV-1. HIV-1 M group subtype C dominates the global pandemic, and there is much speculation that it is more transmissible than other subtypes, but solid data on transmissibility variations between subtypes are rare. Human population densities, access to prevention and treatment, prevalence of genital ulcers, iatrogenic transmissions, and other confounding host factors are all possible reasons why one subtype has spread more than another.


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InternalMed_Harrison. Figure 226-6 schematically diagrams the worldwide distribution of HIV-1 subtypes by region. Seven strains account for the vast majority of HIV infections globally: HIV-1 subtypes A, B, C, D, G and two of the CRFs, CRF01_AE and CRF02_AG. Subtype C viruses (of the M group) are by far the most common form worldwide, likely accounting for ~50% of prevalent infections worldwide. In sub-Saharan Africa, home to approximately two-thirds of all individuals living with HIV/AIDS, the majority of infections are caused by Human Immunodeficiency Virus Disease: AIDS and Related Disorders