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InternalMed_Harrison. FIGuRE 226-6 Global geographic distribution of HIV-1 subtypes and recombinant forms. Distributions derived from relative frequency of subtypes among >500,000 HIV genomic sequences in the Los Alamos National Laboratory HIV Sequence Database. (Additional information available at www.hiv.lanl.gov/components/sequence/HIV/geo/geo.comp.) subtype C, with smaller proportions of infections caused by subtype A, subtype G, CRF02_AG, and other subtypes and recombinants. In South Africa, the country with the largest number of prevalent infections (6.3 million in 2013), >97% of the HIV-1 isolates sequenced are of subtype C. In Asia, HIV-1 isolates of the CRF01_AE lineage and subtypes C and B predominate. CRF01_AE accounts for most infections in south and southeast Asia, while >95% of infections in India, home to an estimated 2.1 million HIV-infected individuals, are of subtype C (see “HIV Infection and AIDS Worldwide,” below). Subtype B viruses are the overwhelmingly predominant viruses seen in the


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InternalMed_Harrison. home to an estimated 2.1 million HIV-infected individuals, are of subtype C (see “HIV Infection and AIDS Worldwide,” below). Subtype B viruses are the overwhelmingly predominant viruses seen in the United States, Canada, certain countries in South America, western Europe, and Australia. It is thought that, purely by chance, subtype B was seeded into the United States and Europe in the late 1970s, thereby establishing an overwhelming founder effect. Many countries have co-circulating viral subtypes that are giving rise to new CRFs. Sequence analyses of HIV-1 isolates from infected individuals indicate that recombination among viruses of different clades likely occurs as a result of infection of an individual with viruses of more than one subtype, particularly in geographic areas where subtypes overlap, and more often in sub-epidemics driven by IV drug use than in those driven by sexual transmission.


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InternalMed_Harrison. The extraordinary diversity of HIV, reflected by the presence of multiple subtypes, circulating recombinant forms, and continuous viral evolution, has implications for possible differential rates of transmission, rates of disease progression, responses to therapy, and the development of resistance to antiretroviral drugs. This diversity is also a formidable obstacle to HIV vaccine development, as a broadly useful vaccine would need to induce protective responses against a wide range of viral strains.


InternalMed_Harrison

InternalMed_Harrison. HIV is transmitted primarily by sexual contact (both heterosexual and male to male); by blood and blood products; and by infected mothers to infants intrapartum, perinatally, or via breast milk. After more than 30 years of experience and observations regarding other potential modalities of transmission, there is no evidence that HIV is transmitted by casual contact or that the virus can be spread by insects, such as by a mosquito bite. Table 226-3 lists the estimated risk of HIV transmission for various types of exposures.


InternalMed_Harrison

InternalMed_Harrison. HIV infection is predominantly a sexually transmitted infection (STI) worldwide. By far the most common mode of infection, particularly in developing countries, is heterosexual transmission, although in many western countries a resurgence of male-to-male sexual transmission has occurred. Although a wide variety of factors including viral load and the presence of ulcerative genital diseases influence the efficiency of heterosexual transmission of HIV, such transmission is generally inefficient. A recent systemic review found a low per-act risk of heterosexual transmission in the absence of antiretrovirals: 0.04% for female-to-male transmission and 0.08% for male-to-female transmission during vaginal intercourse in the absence of antiretroviral therapy or condom use (Table 226-3).


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InternalMed_Harrison. HIV has been demonstrated in seminal fluid both within infected mononuclear cells and in cell-free material. The virus appears to concentrate in the seminal fluid, particularly in situations where there are increased numbers of lymphocytes and monocytes in the fluid, TABLE 226-3 EsTIMATEd PER-ACT PROBABILITy OF ACquIRIng HIv FROM An InFECTEd sOuRCE, By ExPOsuRE ACT Type of Exposure Risk per 10,000 Exposures aHIV transmission through these exposure routes is technically possible but unlikely and not well documented. Sources: CDC, www.cdc.gov/hiv/policies/law/risk.html; P Patel: AIDS 28:1509, 2014.


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InternalMed_Harrison. as in genital inflammatory states such as urethritis and epididymitis, conditions closely associated with other STIs. The virus has also been demonstrated in cervical smears and vaginal fluid. There is an elevated risk of HIV transmission associated with unprotected receptive anal intercourse (URAI) among both men and women compared to the risk associated with receptive vaginal intercourse. Although data are limited, the per-act risk for HIV transmission via URAI has been estimated to be ~1.4% (Table 226-3). The risk of HIV acquisition associated with URAI is probably higher than that seen in penile-vaginal intercourse because only a thin, fragile rectal mucosal membrane separates the deposited semen from potentially susceptible cells in and beneath the mucosa, and micro-trauma of the mucosal membrane may be associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of infection. It is likely that anal


InternalMed_Harrison

InternalMed_Harrison. of the mucosal membrane may be associated with anal intercourse. Anal douching and sexual practices that traumatize the rectal mucosa also increase the likelihood of infection. It is likely that anal intercourse provides at least two modalities of infection: (1) direct inoculation into blood in cases of traumatic tears in the mucosa; and (2) infection of susceptible target cells, such as Langerhans cells, in the mucosal layer in the absence of trauma. Insertive anal intercourse also confers an increased risk of HIV acquisition compared to insertive vaginal intercourse. Although the vaginal mucosa is several layers thicker than the rectal mucosa and less likely to be traumatized during intercourse, the virus can be transmitted to either partner through vaginal intercourse. As noted in Table 226-3, male-to-female HIV transmission is usually more efficient than female-to-male transmission. The differences in reported transmission rates between men and women may be due in part to the


InternalMed_Harrison

InternalMed_Harrison. Table 226-3, male-to-female HIV transmission is usually more efficient than female-to-male transmission. The differences in reported transmission rates between men and women may be due in part to the prolonged exposure to infected seminal fluid of the vaginal and cervical mucosa, as well as the endometrium (when semen enters through the cervical os). By comparison, the penis and urethral orifice are exposed relatively briefly to infected vaginal fluid. Among various cofactors examined in studies of heterosexual HIV transmission, the presence of other STIs has been strongly associated with HIV transmission. In this regard, there is a close association between genital ulcerations and transmission, owing to both susceptibility to infection and infectivity. Infections with microorganisms such as Treponema pallidum (Chap. 206), Haemophilus ducreyi (Chap. 182), and herpes simplex virus (HSV; Chap. 216) are important causes of genital ulcerations linked to transmission of HIV. In addition,


InternalMed_Harrison

InternalMed_Harrison. as Treponema pallidum (Chap. 206), Haemophilus ducreyi (Chap. 182), and herpes simplex virus (HSV; Chap. 216) are important causes of genital ulcerations linked to transmission of HIV. In addition, pathogens responsible for non-ulcerative inflammatory STIs such as those caused by Chlamydia trachomatis (Chap. 213), Neisseria gonorrhoeae (Chap. 181), and Trichomonas vaginalis (Chap. 254) also are associated with an increased risk of transmission of HIV infection. Bacterial vaginosis, an infection related to sexual behavior, but not strictly an STI, also may be linked to an increased risk of transmission of HIV infection. Several studies suggest that treating other STIs and genital tract syndromes may help prevent transmission of HIV. This effect is most prominent in populations in which the prevalence of HIV infection is relatively low. It is noteworthy that this principle may not apply to the treatment of HSV infections since it has been shown that even following anti-HSV therapy with


InternalMed_Harrison

InternalMed_Harrison. prevalence of HIV infection is relatively low. It is noteworthy that this principle may not apply to the treatment of HSV infections since it has been shown that even following anti-HSV therapy with resulting healing of HSV-related genital ulcers, HIV acquisition is not reduced. Biopsy studies revealed the likely explanation is that HIV receptor–positive inflammatory cells persisted in the genital tissue despite the healing of ulcers, and so HIV-susceptible targets remained at the site.


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InternalMed_Harrison. The quantity of HIV-1 in plasma is a primary determinant of the risk of HIV-1 transmission. In a cohort of heterosexual couples in Uganda discordant for HIV infection and not receiving antiretroviral therapy, the mean serum HIV RNA level was significantly higher among HIV-infected subjects whose partners seroconverted than among those whose partners did not seroconvert. In fact, transmission was rare when the infected partner had a plasma level of <1700 copies of HIV RNA per milliliter, even when genital ulcer disease was present (Fig. 226-7). The rate of HIV transmission per coital act was highest during the early stage of HIV infection when plasma HIV RNA levels were high and in advanced disease as the viral set point increased.


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InternalMed_Harrison. Antiretroviral therapy dramatically reduces plasma viremia in most HIV-infected individuals (see “Treatment,” below) and is associated with a reduction in risk of transmission. In a large study of serodiscordant couples, earlier treatment of the HIV-infected partner with among monogamous, heterosexual, HIV-serodiscordant couples in Uganda. (From RH Gray et al: Lancet 357:1149, 2001.) antiretroviral therapy rather than treatment delayed until the CD4+ T cells count fell below 250 cells per μL was associated with a 96% reduction in HIV transmission to the uninfected partner. This approach has been widely referred to as treatment as prevention or TasP. Several studies also have suggested a beneficial effect of antiretroviral treatment at the community level.


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InternalMed_Harrison. A number of studies including large, randomized, controlled trials clearly have indicated that male circumcision is associated with a lower risk of acquisition of HIV infection for heterosexual men. Studies are conflicting as to whether circumcision protects against HIV acquisition among men who have sex with men, but data suggest that circumcision is protective in those men who have sex with men who are insertive only. The benefit of circumcision may be due to increased susceptibility of uncircumcised men to ulcerative STIs, as well as to other factors such as microtrauma to the foreskin and glans penis. In addition, the highly vascularized inner foreskin tissue contains a high density of Langerhans cells as well as increased numbers of CD4+ T cells, macrophages, and other cellular targets for HIV. Finally, the moist environment under the foreskin may promote the presence or persistence of microbial flora that, via inflammatory changes, may lead to even higher concentrations of


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InternalMed_Harrison. targets for HIV. Finally, the moist environment under the foreskin may promote the presence or persistence of microbial flora that, via inflammatory changes, may lead to even higher concentrations of target cells for HIV in the foreskin. In addition, randomized trials have demonstrated that male circumcision also reduces hepatitis C virus (HCV) type 2, human papillomavirus virus (HPV), and genital ulcer disease in men as well as HPV, genital ulcer disease, bacterial vaginosis, and Trichomonas vaginalis infections among female partners of circumcised men. Thus, there may be an added benefit of diminution of risk for HIV acquisition to the female sexual partners of circumcised men.


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InternalMed_Harrison. In some studies the use of oral contraceptives was associated with an increase in incidence of HIV infection over and above that which might be expected by not using a condom for birth control. This phenomenon may be due to drug-induced changes in the cervical mucosa, rendering it more vulnerable to penetration by the virus. Adolescent girls might also be more susceptible to infection upon exposure due to the properties of an immature genital tract with increased cervical ectopy or exposed columnar epithelium. Oral sex is a much less efficient mode of transmission of HIV than is anal intercourse or vaginal intercourse (Table 226-3). A number of studies have reported that the incidence of transmission of infection by oral sex among couples discordant for HIV was extremely low. However, there have been well-documented reports of HIV transmission that likely resulted from fellatio or cunnilingus. Therefore, the assumption that oral sex is completely safe is not warranted.


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InternalMed_Harrison. The association of alcohol consumption and illicit drug use with unsafe sexual behavior, both homosexual and heterosexual, leads to an increased risk of sexual transmission of HIV. Methamphetamine and other so-called club drugs (e.g., ecstasy, ketamine, and gamma hydroxybutyrate), sometimes taken in conjunction with PDE-5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra), have been associated with risky sexual practices and increased risk of HIV infection, particularly among men who have sex with men.


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1222 TRANSMISSION THROuGH INJECTION DRuG uSE HIV can be transmitted to injection drug users (IDUs) who are exposed to HIV while sharing injection paraphernalia such as needles, syringes, the water in which drugs are mixed, or the cotton through which drugs are filtered. Parenteral transmission of HIV during injection drug use does not require IV puncture; SC (“skin popping”) or IM (“muscling”) injections can transmit HIV as well, even though these behaviors are sometimes erroneously perceived as low-risk. Among IDUs, the risk of HIV infection increases with the duration of injection drug use; the frequency of needle sharing; the number of partners with whom paraphernalia are shared, particularly in the setting of “shooting galleries” where drugs are sold and large numbers of IDUs may share a limited number of “works”; comorbid psychiatric conditions such as antisocial personality disorder; the use of cocaine in


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InternalMed_Harrison. galleries” where drugs are sold and large numbers of IDUs may share a limited number of “works”; comorbid psychiatric conditions such as antisocial personality disorder; the use of cocaine in injectable form or smoked as “crack”; and the use of injection drugs in a geographic location with a high prevalence of HIV infection, such as certain inner-city areas in the United States. As noted in Table 226-3, the per-act risk of transmission from injection drug use with a contaminated needle has been estimated to be approximately 0.6%.


InternalMed_Harrison

InternalMed_Harrison. HIV can be transmitted to individuals who receive HIV-tainted blood transfusions, blood products, or transplanted tissue. The first cases of AIDS among transfusion recipients and individuals with hemophilia or other clotting disorders were reported in 1982. The vast majority of HIV infections acquired via contaminated blood transfusions, blood components, or transplanted tissue in resource-rich countries occurred prior to the spring of 1985, when mandatory testing of donated blood for HIV-1 was initiated. It is estimated that >90% of individuals exposed to HIV-contaminated blood products become infected (Table 226-3). Although blood screening for HIV is becoming more universal even in the developing world, unfortunately, in some resource-poor countries, HIV continues to be transmitted by blood, blood products, and tissues due to inadequate screening. Transfusions of whole blood, packed red blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. In


InternalMed_Harrison

InternalMed_Harrison. blood products, and tissues due to inadequate screening. Transfusions of whole blood, packed red blood cells, platelets, leukocytes, and plasma are all capable of transmitting HIV infection. In contrast, hyperimmune gamma globulin, hepatitis B immune globulin, plasma-derived hepatitis B vaccine, and Rho immune globulin have not been associated with transmission of HIV infection. The procedures involved in processing these products either inactivate or remove the virus.


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InternalMed_Harrison. Currently, in the United States and in most developed countries, the following measures have made the risk of transmission of HIV infection by transfused blood or blood products extremely small: the screening of blood donations for antibodies to HIV-1 and HIV-2 and determination of the presence of HIV nucleic acid usually in mini-pools of several specimens; the careful selection of potential blood donors with health history questionnaires to exclude individuals with risk behavior; and opportunities for self-deferral and the screening out of HIV-negative individuals with serologic testing for infections that have shared risk factors with HIV, such as hepatitis B and C and syphilis. The chance of infection of a hemophiliac via clotting factor concentrates has essentially been eliminated because of the added layer of safety resulting from heat treatment of the concentrates. It is currently estimated that the risk of infection with HIV in the United States via transfused screened blood is


InternalMed_Harrison

InternalMed_Harrison. of the added layer of safety resulting from heat treatment of the concentrates. It is currently estimated that the risk of infection with HIV in the United States via transfused screened blood is approximately 1 in 2 million units. Therefore, since ~16 million donations are collected in the United States each year, despite the best efforts of science, one cannot completely eliminate the risk of transfusion-related transmission of HIV. In this regard, a case of transfusion-related transmission of HIV was reported in the United States in 2010, which was tracked to a blood donation in 2008; this was the first such reported case since 2002. Transmission of HIV (both HIV-1 and HIV-2) by blood or blood products is still an ongoing threat in certain developing countries, particularly in sub-Saharan Africa, where routine screening of blood is not universally practiced. In other countries, there have been reports of sporadic breakdowns in routinely available screening procedures in which


InternalMed_Harrison

InternalMed_Harrison. Africa, where routine screening of blood is not universally practiced. In other countries, there have been reports of sporadic breakdowns in routinely available screening procedures in which contaminated blood was allowed to be transfused, resulting in small clusters of patients becoming infected. For example, in China in the 1990s, a disturbingly large number of persons became infected by selling blood in situations where the collectors reused needles that were contaminated and, in some instances, mixed blood products from a number of individuals, separated the plasma, and reinfused mixed red blood cells back into the individual donors.


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InternalMed_Harrison. OCCuPATIONAL TRANSMISSION OF HIV: HEALTH CARE WORKERS, LABORATORY WORKERS, AND THE HEALTH CARE SETTING There is a small but definite occupational risk of HIV transmission to health care workers and laboratory personnel and potentially others who work with HIV-containing materials, particularly when sharp objects are used. An estimated 600,000 to 800,000 health care workers are stuck with needles or other sharp medical instruments in the United States each year. The global number of HIV infections among health care workers attributable to sharps injuries has been estimated to be 1000 cases (range, 200–5000) per year. As of 2010, there had been 57 documented cases of occupational HIV transmission to health care workers in the United States and 143 possible transmissions. There have been no confirmed cases reported since 1999.


InternalMed_Harrison

InternalMed_Harrison. Exposures that place a health care worker at potential risk of HIV infection are percutaneous injuries (e.g., a needle stick or cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other potentially infectious body fluids. Large, multi-institutional studies have indicated that the risk of HIV transmission following skin puncture from a needle or a sharp object that was contaminated with blood from a person with documented HIV infection is ~0.3% and after a mucous membrane exposure it is 0.09% (see “HIV and the Health Care Worker,” below) if the injured and/or exposed person is not treated within 24 h with antiretroviral drugs. The risk of hepatitis B virus (HBV) infection following a similar type of exposure is ~6–30% in nonimmune individuals; if a susceptible worker is exposed to HBV, postexposure prophylaxis with hepatitis B immune globulin and initiation of HBV


InternalMed_Harrison

InternalMed_Harrison. following a similar type of exposure is ~6–30% in nonimmune individuals; if a susceptible worker is exposed to HBV, postexposure prophylaxis with hepatitis B immune globulin and initiation of HBV vaccine is >90% effective in preventing HBV infection. The risk of HCV infection following percutaneous injury is ~1.8% (Chap. 360).


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InternalMed_Harrison. Rare HIV transmission after nonintact skin exposure has been documented, but the average risk for transmission by this route has not been precisely determined; however, it is estimated to be less than the risk for mucous membrane exposure. Transmission of HIV through intact skin has not been documented. Currently in developed countries, virtually all puncture wounds and mucous membrane exposures in health care workers involving blood from a patient with documented HIV infection are treated prophylactically with combination antiretroviral therapy (cART). This practice, referred to as postexposure prophylaxis or PEP, has dramatically reduced the occurrence of puncture-related transmissions of HIV to health care workers.


InternalMed_Harrison

InternalMed_Harrison. In addition to blood and visibly bloody body fluids, semen and vaginal secretions also are considered potentially infectious; however, they have not been implicated in occupational transmission from patients to health care workers. The following fluids also are considered potentially infectious: cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid. The risk for transmission after exposure to fluids or tissues other than HIV-infected blood also has not been quantified, but it is probably considerably lower than the risk after blood exposures. Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious for HIV unless they are visibly bloody. Rare cases of HIV transmission via human bites have been reported, but not in the setting of occupational exposure.


InternalMed_Harrison

InternalMed_Harrison. An increased risk for HIV infection following percutaneous exposures to HIV-infected blood is associated with exposures involving a relatively large quantity of blood, as in the case of a device visibly contaminated with the patient’s blood, a procedure that involves a hollow-bore needle placed directly in a vein or artery, or a deep injury. Factors that might be associated with mucocutaneous transmission of HIV include exposure to an unusually large volume of blood and prolonged contact. In addition, the risk increases for exposures to blood from untreated patients with advanced-stage disease or those patients in the acute stage of HIV infection, owing to the higher levels of HIV in the blood under those circumstances. Since the beginning of the HIV epidemic, there have been rare instances where transmission of infection from a health care worker to patients seemed highly probable. Despite these small number of documented cases, the risk of HIV transmission involving health care


InternalMed_Harrison

InternalMed_Harrison. where transmission of infection from a health care worker to patients seemed highly probable. Despite these small number of documented cases, the risk of HIV transmission involving health care workers (infected or not) to patients is extremely low in developed countries—in fact, too low to be measured accurately. In this regard, several epidemiologic studies have been performed tracing thousands of patients of HIV-infected dentists, physicians, surgeons, obstetricians, and gynecologists, and no other cases of HIV transmission that could be linked to the health care providers were identified.


InternalMed_Harrison

InternalMed_Harrison. Breaches in infection control and the reuse of contaminated syringes, failure to properly sterilize surgical instruments, and/or hemodialysis equipment have also resulted rarely in the transmission of HIV from patient to patient in hospitals, nursing homes, and outpatient settings. Finally, these very rare occurrences of transmission of HIV as well as HBV and HCV to and from health care workers in the workplace underscore the importance of the use of universal precautions when caring for all patients (see below and Chap. 168).


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InternalMed_Harrison. HIV infection can be transmitted from an infected mother to her fetus during pregnancy, during delivery, or by breast-feeding. This remains an important form of transmission of HIV infection in certain developing countries, where the proportion of infected women to infected men is ~1:1. Virologic analyses of aborted fetuses indicate that HIV can be transmitted to the fetus during the first or second trimesters of pregnancy. However, maternal transmission to the fetus occurs most commonly in the perinatal period. Two studies performed in Rwanda and the Democratic Republic of Congo (then called Zaire) indicated that among all mother-to-child transmissions of HIV, the relative proportions were 23–30% before birth, 50–65% during birth, and 12–20% via breast-feeding.


InternalMed_Harrison

InternalMed_Harrison. In the absence of prophylactic antiretroviral therapy to the mother during pregnancy, labor, and delivery, and to the fetus following birth, the probability of transmission of HIV from mother to infant/ fetus ranges from 15% to 25% in industrialized countries and from 25% to 35% in developing countries. These differences may relate to the adequacy of prenatal care as well as to the stage of HIV disease and the general health of the mother during pregnancy. Higher rates of transmission have been reported to be associated with many factors—the best documented of which is the presence of high maternal levels of plasma viremia, with the risk increasing linearly with the level of maternal plasma viremia. It is very unlikely that mother-tochild transmission will occur if the mother’s level of plasma viremia is <1000 copies of HIV RNA/mL of blood and extremely unlikely if the level is undetectable (i.e., <50 copies/mL). However, there may not be a lower “threshold” below which transmission


InternalMed_Harrison

InternalMed_Harrison. plasma viremia is <1000 copies of HIV RNA/mL of blood and extremely unlikely if the level is undetectable (i.e., <50 copies/mL). However, there may not be a lower “threshold” below which transmission never occurs, since certain studies have reported rare transmission by women with viral RNA levels <50 copies/mL. Increased mother-to-child transmission is also correlated with closer human leukocyte antigen (HLA) match between mother and child. A prolonged interval between membrane rupture and delivery is another well-documented risk factor for transmission. Other conditions that are potential risk factors, but that have not been consistently demonstrated, are the presence of chorioamnionitis at delivery; STIs during pregnancy; illicit drug use during pregnancy; cigarette smoking; preterm delivery; and obstetric procedures such as amniocentesis, amnioscopy, fetal scalp electrodes, and episiotomy. In a seminal study conducted in the United States and France in the 1990s, zidovudine


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InternalMed_Harrison. delivery; and obstetric procedures such as amniocentesis, amnioscopy, fetal scalp electrodes, and episiotomy. In a seminal study conducted in the United States and France in the 1990s, zidovudine treatment of HIV-infected pregnant women from the beginning of the second trimester through delivery and of the infant for 6 weeks following birth dramatically decreased the rate of intrapartum and perinatal transmission of HIV infection from 22.6% in the untreated group to <5%. Today, the rate of motherto-child transmission has fallen to 1% or less in pregnant women who are receiving combination antiretroviral therapy (cART) for their HIV infection. Such treatment, combined with cesarean section delivery, has rendered mother-to-child transmission of HIV an unusual event in the United States and other developed nations. In this regard, both the United States Public Health Service and the World Health Organization guidelines recommend that all pregnant HIV-infected 1223 women should receive


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InternalMed_Harrison. other developed nations. In this regard, both the United States Public Health Service and the World Health Organization guidelines recommend that all pregnant HIV-infected 1223 women should receive cART for the health of the mother and to prevent perinatal transmission regardless of plasma HIV RNA copy number or CD4+ T cell counts.


InternalMed_Harrison

InternalMed_Harrison. Breast-feeding is an important modality of transmission of HIV infection in developing countries, particularly where mothers continue to breast-feed for prolonged periods. The risk factors for mother-tochild transmission of HIV via breast-feeding are not fully understood; factors that increase the likelihood of transmission include detectable levels of HIV in breast milk, the presence of mastitis, low maternal CD4+ T cell counts, and maternal vitamin A deficiency. The risk of HIV infection via breast-feeding is highest in the early months of breast-feeding. In addition, exclusive breast-feeding has been reported to carry a lower risk of HIV transmission than mixed feeding. In developed countries, breast feeding of babies by an HIV-infected mother is contraindicated since alternative forms of adequate nutrition, i.e., formulas, are readily available. In developing countries, where breast-feeding may be essential for the overall health of the infant, the continuation of cART in the


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InternalMed_Harrison. of adequate nutrition, i.e., formulas, are readily available. In developing countries, where breast-feeding may be essential for the overall health of the infant, the continuation of cART in the infected mother during the period of breastfeeding markedly diminishes the risk of transmission of HIV to the infant. In fact, once cART has been initiated in a pregnant woman, many experts recommend that therapy be continued for life.


InternalMed_Harrison

InternalMed_Harrison. Although HIV can be isolated typically in low titers from saliva of a small proportion of infected individuals, there is no convincing evidence that saliva can transmit HIV infection, either through kiss ing or through other exposures, such as occupationally to health care workers. Saliva contains endogenous antiviral factors; among these factors, HIV-specific immunoglobulins of IgA, IgG, and IgM isotypes are detected readily in salivary secretions of infected individuals. It has been suggested that large glycoproteins such as mucins and thrombospondin 1 sequester HIV into aggregates for clearance by the host. In addition, a number of soluble salivary factors inhibit HIV to various degrees in vitro, probably by targeting host cell receptors rather than the virus itself. Perhaps the best studied of these, secretory leukocyte protease inhibitor (SLPI), blocks HIV infection in several cell culture systems, and it is found in saliva at levels that approximate those required for inhibition


InternalMed_Harrison

InternalMed_Harrison. of these, secretory leukocyte protease inhibitor (SLPI), blocks HIV infection in several cell culture systems, and it is found in saliva at levels that approximate those required for inhibition of HIV in vitro. In this regard, higher salivary levels of SLPI in breast-fed infants were associated with a decreased risk of HIV transmission through breast milk. It has also been suggested that submandibular saliva reduces HIV infectivity by stripping gp120 from the surface of virions, and that saliva-mediated disruption and lysis of HIV-infected cells occurs because of the hypotonicity of oral secretions. There have been outlier cases of suspected transmission by saliva, but these have probably been blood-to-blood transmissions. Transmission of HIV by a human bite can occur but is a rare event. Although virus can be identified, if not isolated, from virtually any body fluid, there is no evidence that HIV transmission can occur as a result of exposure to tears, sweat, or urine. However,


InternalMed_Harrison

InternalMed_Harrison. Although virus can be identified, if not isolated, from virtually any body fluid, there is no evidence that HIV transmission can occur as a result of exposure to tears, sweat, or urine. However, there have been isolated cases of transmission of HIV infection by body fluids that may or may not have been contaminated with blood. Most of these situations occurred in the setting of a close relative providing intensive nursing care for an HIV-infected person without observing universal precautions, underscoring the importance of adhering to such precautions in the handling of body fluids and wastes from HIV-infected individuals.


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InternalMed_Harrison. HIV INFECTION AND AIDS WORLDWIDE HIV infection/AIDS is a global pandemic, with cases reported from virtually every country. At the end of 2013, an estimated 35.0 million individuals were living with HIV infection, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). An estimated 95% of people living with HIV/AIDS reside in lowand middle-income countries; ~50% are female, and 3.2 million are children <15 years. The distribution of these cases is illustrated in Fig. 226-8. The estimated number of people living with HIV—i.e., Human Immunodeficiency Virus Disease: AIDS and Related Disorders


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders FIGuRE 226-8 Estimated number of adults and children living with HIV infection as of December, 2013. Total: 35.0 (33.2 million–37.2 million). (From Joint United Nations Programme on HIV/AIDS [UNAIDS].) the global prevalence—has increased more than fourfold since 1990, reflecting the combined effects of continued high rates of new HIV infections and the life-prolonging impact of antiretroviral therapy (Fig. 226-9). In 2013, the global prevalence rate among persons age 15–49 years was 0.8%, with rates varying widely by country and region as illustrated in Fig. 226-10.


InternalMed_Harrison

InternalMed_Harrison. In 2013, an estimated 2.1 million new cases of HIV infection occurred worldwide, including 240,000 among children <15 years; about 40% of new infections were among persons under age 25. Between 2001 and 2013, the estimated number of new HIV infections globally fell by 38% (Fig. 226-9). Recent reductions in global HIV incidence likely reflect progress with HIV prevention efforts and the increased provision to HIV-infected people of antiretroviral therapy, which makes them much less likely to transmit the virus to sexual partners. In 2013, global AIDS deaths totaled 1.5 million (including 190,000 children <15 years), a 35% decrease since 2005 that coincides with a rapid expansion of access to antiretroviral therapy (Fig. 226-9). Since the beginning of the pandemic, an estimated 39 million people have died of an AIDS-related illness.


InternalMed_Harrison

InternalMed_Harrison. The HIV epidemic has occurred in “waves” in different regions of the world, each wave having somewhat different characteristics depending on the demographics of the country and region in question and the timing of the introduction of HIV into the population. Although the AIDS epidemic was first recognized in the United States and shortly thereafter in Western Europe, it very likely began in sub-Saharan Africa (see above), which has been particularly devastated by the epidemic. More than 70% of all people with HIV infection (~25 million), and nearly 90% of all HIV-infected children live in that region, even though sub-Saharan Africa is home to just 12% of the world’s population (Fig. 226-8). Within the region, southern Africa is worst-affected. In nine southern African countries, seroprevalence data indicate that >10% of the adult population age 15–49 is HIV-infected (Fig. 226-10). In addition, among high-risk individuals (e.g., commercial sex workers, patients attending STI clinics)


InternalMed_Harrison

InternalMed_Harrison. data indicate that >10% of the adult population age 15–49 is HIV-infected (Fig. 226-10). In addition, among high-risk individuals (e.g., commercial sex workers, patients attending STI clinics) who live in urban areas of sub-Saharan Africa, seroprevalence is now >50% in some places. Recent data offer promising signs of declining HIV incidence and prevalence in many countries in the region, although frequently at levels that remain high. Heterosexual exposure is


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InternalMed_Harrison. New HIV infections and deaths due to AIDS (millions) People living with HIV infection (millions) FIGuRE 226-9 Global estimates of HIV incidence and AIDS deaths (left) and, HIV prevalence (right), 1990–2013. (From UNAIDS.) 15.0% – 27.4% 5.0%– <15.0% 1.0% – <5.0% 0.5% – <1.0% Global Adult HIV Prevalence Rate = 0.8% 0.1% – <0.5% <0.1% No data FIGuRE 226-10 Global adult HIV prevalence rate, 2013. Data are estimates for adults aged 15-49 years. (From UNAIDS.) the primary mode of HIV transmission in sub-Saharan Africa, with women and girls disproportionately affected, accounting for ~60 percent of all HIV infections in that region. In 2013, an estimated 230,000 people were living with HIV in the Middle East/North Africa region. Cases are largely concentrated among IDUs, men who have sex with men, and sex workers and their clients.


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InternalMed_Harrison. In Asia and the Pacific, an estimated 4.8 million people were living with HIV at the end of 2013. In this region of the world, HIV prevalence is highest in southeast Asian countries, with wide variation in trends between different countries. Among countries in Asia, only Thailand has an adult seroprevalence rate of >1%. However, the populations of many Asian nations are so large (especially India and China) that even low infection and seroprevalence rates result in large numbers of people living with HIV. Although Asia’s epidemic has been concentrated for some time among specific populations—sex workers and their clients, men who have sex with men, and IDUs—it is expanding to the heterosexual partners of those most at risk.


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InternalMed_Harrison. The epidemic is expanding in Eastern Europe and Central Asia, where ~1.1 million people were living with HIV at the end of 2013. The Russian Federation and Ukraine account for the majority of HIV cases in the region. Driven initially by injection drug use and increasingly by heterosexual transmission, the number of new infections in this region has increased dramatically over the past decade. Approximately 1.9 million people are living with HIV/AIDS in Central and South America and the Caribbean. Brazil is home to the largest number of HIV-infected people in the region. However, the epidemic has been slowed in that country due to successful treatment and prevention efforts. Men who have sex with men account for the largest proportion of HIV infections in Central and South America. The Caribbean region has the highest regional adult seroprevalence rate after Africa. Heterosexual transmission, often tied to sex work, is the main driver of transmission in the region.


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InternalMed_Harrison. Approximately 2.3 million people are living with HIV/AIDS in North America and western and central Europe. The number of new infections among men who have sex with men has increased over the past decade in these mostly high-income areas, while rates of new infections among heterosexuals have stabilized and infections among women and IDUs have fallen. About 1.7 million people have been infected with HIV in the United States since the beginning of the epidemic, of whom >630,000 have died. Approximately 1.1 million individuals in the United States are living with HIV infection, ~16–18% of whom are unaware of their infection, according to recent estimates. As illustrated in Fig. 226-11, only a fraction of HIV-infected people are able to negotiate the steps in the HIV “care continuum,” from diagnosis, to entering into and staying in care, to receiving antiretroviral therapy, and ultimately to achieving a suppressed viral load (see “Treatment,” below).


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InternalMed_Harrison. More than 60% of those living with HIV/AIDS are Black/African-American or Hispanic/Latino, and more than half are men who have sex with men. The estimated HIV seroprevalence rate among all individuals age 13 years or older in the United States is ~0.5%. Approximately 2% of Black/African-American adults are HIV-infected in the United States, higher than any other group.


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InternalMed_Harrison. The number of new HIV infections in the United States, HIV incidence, peaked at about 130,000 per year in the late 1980s, followed by declines. For more than a decade, HIV incidence has remained stable at approximately 50,000 per year, with the proportion of new infections increasing in recent years among men who have sex with men and falling among women and IDUs. Among adults and adolescents newly diagnosed with HIV infection in 2011 (regardless of stage of infection), ~79% were males and ~21% were women. Of new HIV diagnoses among men, ~79% were attributed to male-to-male sexual contact, ~12% to heterosexual contact, ~6% to injection drug use, and ~4% to a combination of male-to-male sexual contact and injection drug use. Of new HIV diagnoses among women, ~86% were due to heterosexual contact and ~14% to injection drug use 82% 66% 37% 33% 25% 290,924 1,148,200 HIV-infected HIV-Linked to Retained in Prescribed Suppressed diagnosed HIV care HIV care ART viral load


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InternalMed_Harrison. HIV-infected HIV-Linked to Retained in Prescribed Suppressed diagnosed HIV care HIV care ART viral load FIGuRE 226-11 Estimated percentage of HIV-infected people engaged in selected stages of the continuum of HIV care in the United States. (Adapted from HI Hall et al: JAMA Intern Med 173:1337, 2013.) Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1226 Males Females n = 38,825 n = 10,257 FIGuRE 226-12 Transmission categories of adults and adolescents diagnosed with HIV infection (regardless of stage) in 2011, United States. (From CDC.) (Fig. 226-12). The estimated numbers of new HIV infections in 2011 in the United States for the 10 most affected subpopulations are shown in Fig. 226-13. Perinatal HIV transmission, from an HIV-infected mother to her baby, has declined significantly in the United States, largely due to Number of new HIV infections 2000 4000 6000 8000 10000 12000 Number of inf ections


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InternalMed_Harrison. Number of new HIV infections 2000 4000 6000 8000 10000 12000 Number of inf ections FIGuRE 226-13 Estimated number of new HIV infections in the United States, 2011, for the most affected subpopulations. FIGuRE 226-14 Estimated number of HIV-infected infants, United (From CDC.) States, 1990–2010. (From CDC.) the implementation of guidelines for the universal counseling and voluntary HIV testing of pregnant women and the use of antiretroviral therapy for pregnant women and newborn infants to prevent infection (Fig. 226-14). In 2011, fewer than 200 children were diagnosed with HIV infection in the United States.


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InternalMed_Harrison. HIV infection and AIDS have disproportionately affected minority populations in the United States. Among those diagnosed with HIV (regardless of stage of infection) in 2011, 47% percent were Blacks/ African Americans, a group that constitutes only 12% of the U.S. population (Fig. 226-15A). The estimated rate of new HIV diagnoses in 2011 by race/ethnicity per 100,000 population in the United States is shown in Fig. 226-15B.


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InternalMed_Harrison. The number of individuals diagnosed with AIDS and deaths among persons with AIDS in the United States rose steadily through the 1980s; AIDS cases peaked in 1993 and deaths in 1995 (Fig. 226-16). Since then, the annual numbers of AIDS-related deaths in the United States have fallen ~70%. This trend is due to several factors, including improved prophylaxis and treatment of opportunistic infections, growing experience among the health professions in caring for HIV-infected individuals, improved access to health care, and a decrease in new infections due to saturational effects and prevention efforts. n = 49,273 However, the most influential factor clearly has been 1227 the increased use of potent antiretroviral drugs, gen-Asian 2% American Indian/ erally administered in a combination of three or fourAlaska Native


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InternalMed_Harrison. American Indian/ erally administered in a combination of three or fourAlaska Native Native Hawaiian/ agents. Other Pacific Islander <1% Although the HIV/AIDS epidemic on the whole is <1% plateauing in the United States, it is spreading rapidly among certain populations, stabilizing in others, and decreasing in others. Similar to other STIs, HIV infection will not spread homogeneously throughout the population of the United States. However, it is clear that anyone who practices high-risk behavior is at risk for HIV infection. In addition, recent increases in infections and AIDS cases among young men who have sex with men as well as the spread in pockets of poverty in both urban and rural regions (particularly among underserved minority populations in the southern United States with inadequate access to health A care) testify that the epidemic of HIV infection in the United States remains a public health problem of major proportion.


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InternalMed_Harrison. The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells occurring in a setting of polyclonal immune activation. The helper subset of T cells is defined phenotypically by the presence on its surface of the CD4 molecule (Chap. 372e), which serves as the primary cellular receptor for HIV. A co-receptor must also be present together with CD4 for efficient binding, fusion, and entry of HIV-1 into its target cells (Figs. 226-3 and 226-4). HIV uses two major co-receptors, CCR5 and CXCR4, for fusion and entry; these co-receptors are also the primary receptors for certain chemoattractive cytokines termed chemo- kines and belong to the seven-transmembrane-domain G protein–coupled family of receptors. A number of mechanisms responsible for cellular depletion and/or B immune dysfunction of CD4+ T cells have been demonstrated in vitro; these include direct


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InternalMed_Harrison. G protein–coupled family of receptors. A number of mechanisms responsible for cellular depletion and/or B immune dysfunction of CD4+ T cells have been demonstrated in vitro; these include direct infection and FIGuRE 226-15 Race/ethnicity of persons (including children) diagnosed destruction of these cells by HIV, as well as indirect with HIV infection (regardless of stage) during 2011 in the United States. effects such as immune clearance of infected cells, cell


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InternalMed_Harrison. A. Estimated proportion of new infections by race/ethnicity. B. Estimated rate death associated with aberrant immune activation, and of new infections by race/ethnicity (per 100,000 population). (From CDC.) immune exhaustion due to aberrant cellular activation FIGuRE 226-16 Estimated number of AIDS cases and AIDS deaths, United States, 1985–2011. (From CDC.) 0 10 20 304050607080 Rate/100,000 population Human Immunodeficiency Virus Disease: AIDS and Related Disorders No. of cases and deaths (in thousands)


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders No. of cases and deaths (in thousands) FIGuRE 226-17 Typical course of an untreated HIV-infected individual. See text for detailed one other cell. Once infection is estab- lished, the virus replicates in lymphoid cells in the mucosa, the submucosa, and to some extent the lymphoreticular tissues that drain the gut tissues. For a108 variable period of time ranging from a few to several days, the virus cannot yet be detected in the plasma. This period is referred to as the “eclipse” phase of infection. As more virus is produced within 106 several days to weeks, it is disseminated, first to the draining lymph nodes and then to other lymphoid compartments 105 where it has easy access to dense concentrations of CD4+ T cell targets, allowing for a burst of high-level viremia that104 is readily detectable by currently avail- description. (From G Pantaleo et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical


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InternalMed_Harrison. Society. All rights reserved.) with resulting cellular dysfunction. Patients with CD4+ T cell levels below certain thresholds are at high risk of developing a variety of opportunistic diseases, particularly the infections and neoplasms that are AIDS-defining illnesses. Some features of AIDS, such as Kaposi’s sarcoma and certain neurologic abnormalities, cannot be explained completely by the immunodeficiency caused by HIV infection, since these complications may occur prior to the development of severe immunologic impairment.


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InternalMed_Harrison. The combination of viral pathogenic and immunopathogenic events that occurs during the course of HIV disease from the moment of initial (primary) infection through the development of advanced-stage disease is complex and varied. It is important to appreciate that the pathogenic mechanisms of HIV disease are multifactorial and multiphasic and are different at different stages of the disease. Therefore, it is essential to consider the typical clinical course of an untreated HIV-infected individual in order to more fully appreciate these pathogenic events (Fig. 226-17). EARLY EVENTS IN HIV INFECTION: PRIMARY INFECTION AND INITIAL DISSEMINATION OF VIRuS


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InternalMed_Harrison. Using mucosal transmission as a model, the earliest events (within hours) that occur following exposure of HIV to the mucosal surface determine whether an infection will be established as well as the subsequent course of events following infection. Although the mucosal barrier is relatively effective in limiting access of HIV to susceptible targets in the lamina propria, the virus can cross the barrier by transport on Langerhans cells, an epidermal type of DC, just beneath the surface or through microscopic rents in the mucosa. Significant disruptions in the mucosal barrier as seen in ulcerative genital disease facilitate viral entry and increase the efficiency of infection. Virus then seeks susceptible targets, which are primarily CD4+ T cells that are spatially dispersed in the mucosa. This spatial dispersion of targets provides a significant obstacle to the establishment of infection. Such obstacles account for the low efficiency of sexual transmission of HIV (see “Sexual


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InternalMed_Harrison. mucosa. This spatial dispersion of targets provides a significant obstacle to the establishment of infection. Such obstacles account for the low efficiency of sexual transmission of HIV (see “Sexual Transmission,” above). Both “partially” resting CD4+ T cells and activated CD4+ T cells serve as early amplifiers of infection. Resting CD4+ T cells are more abundant; however, activated CD4+ T cells produce larger amounts of virus. In order for infection to become established, the basic reproductive rate (R0) must become equal to or greater than 1, i.e., each infected cell would infect at least able assays (Fig. 226-18). An important lymphoid organ, the gut-associated lymphoid tissue (GALT), is a major target of HIV infection and the location where large numbers of CD4+ T cells (usually memory cells) are infected and depleted, both by direct viral effects and by activation-associated apoptosis. Once virus virus is widely disseminated, infection is firmly established and the process is


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InternalMed_Harrison. cells) are infected and depleted, both by direct viral effects and by activation-associated apoptosis. Once virus virus is widely disseminated, infection is firmly established and the process is irreversible. It is important to point out that the initial infection of susceptible cells may vary somewhat with the route of infection. Virus that enters directly into the bloodstream via infected blood or blood products (i.e., transfusions, use of contaminated needles for injection drugs, sharp-object injuries, maternal-tofetal transmission either intrapartum or perinatally, or sexual intercourse where there is enough trauma to cause bleeding) is likely first cleared from the circulation to the spleen and other lymphoid organs, where primary focal infections begin, followed by wider dissemination throughout other lymphoid tissues as described above.


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InternalMed_Harrison. It has been demonstrated that sexual transmission of HIV is the result of a single infectious event and that a viral genetic bottleneck exists for transmission. In this regard, certain characteristics of the HIV envelope glycoprotein have a major influence on transmission, at least in subtype A and C viruses. Transmitting viruses, often referred to as “founder viruses,” are usually underrepresented in the circulating viremia of the transmitting partner and are less-diverged viruses with signature sequences including shorter V1–V2 loop sequences and fewer predicted N-linked glycosylation sites relative to the major circulating variants. These viruses are almost exclusively R5 strains and are usually sensitive to neutralization by antibody from the transmitting partner. Once replication proceeds in the newly infected partner, the founder virus diverges and accumulates glycosylation sites, becoming progressively more resistant to neutralization (Fig. 226-19).


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InternalMed_Harrison. The acute burst of viremia and wide dissemination of virus in primary HIV infection may be associated with an acute HIV syndrome, which occurs to varying degrees in ~50% of individuals with primary infection (see below). This syndrome is usually associated with high levels of viremia measured in millions of copies of HIV RNA per milliliter of plasma that last for several weeks. Acute mononucleosis-like symptoms are well correlated with the presence of viremia. Virtually all patients develop some degree of viremia during primary infection, which contributes to virus dissemination throughout the lymphoid tissue, even though they may remain asymptomatic or not recall experiencing symptoms. It appears that the initial level of plasma viremia in primary HIV infection does not necessarily determine the rate of disease progression; however, the set point of the level of steady-state plasma viremia after ~1 year does seem to correlate with the slope of disease progression in the untreated


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InternalMed_Harrison. the rate of disease progression; however, the set point of the level of steady-state plasma viremia after ~1 year does seem to correlate with the slope of disease progression in the untreated patient. The strikingly high levels of viremia observed in many patients with acute HIV infection is felt to be associated with a higher likelihood of transmission of the virus


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InternalMed_Harrison. FIGuRE 226-18 Summary of early events in HIV infection. See text for detailed description. CTLs, cytolytic T lymphocytes; HIV, human immunodeficiency virus. (Adapted from AT Haase: Nat Rev Immunol 5:783, 2005.) to others by a variety of routes including sexual transmission, shared needles and syringes, and mother-to-child transmission intrapartum, perinatally, or via breast milk.


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InternalMed_Harrison. ESTABLISHMENT OF CHRONIC AND PERSISTENT INFECTION Persistence of Virus Replication HIV infection is unique among human viral infections. Despite the robust cellular and humoral immune responses that are mounted following primary infection (see “Immune Response to HIV,” below), once infection has been established the virus succeeds in escaping complete immune-mediated clearance, paradoxically seems to thrive on immune activation, and is never eliminated completely from the body. Rather, a chronic infection develops and persists with varying degrees of continual virus replication in the untreated patient for a median of ~10 years before the patient becomes clinically ill (see “Advanced HIV Disease,” below). It is this establishment of a chronic, persistent infection that is the hallmark of HIV disease. Throughout the often protracted course of chronic infection, virus replication can invariably be detected in untreated patients by widely available assays that measure copies of HIV RNA


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InternalMed_Harrison. HIV disease. Throughout the often protracted course of chronic infection, virus replication can invariably be detected in untreated patients by widely available assays that measure copies of HIV RNA per milliliter of plasma. Levels of virus vary greatly in most untreated patients, ranging from several thousand to a few million copies of HIV RNA per milliliter of plasma. Studies using highly sensitive molecular techniques have demonstrated that even in certain


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InternalMed_Harrison. FIGuRE 226-19 As HIV diverges from founder to chronically replicating virus, it accumulates N-linked glycosylation sites. See text for detailed description. (Adapted from CA Derdeyn et al: Science 303:2019, 2004; B Chohan et al: J Virol 79:6528, 2005; and BF Keele et al: Proc Natl Acad Sci USA 105:7552, 2008.) patients in whom plasma viremia is suppressed to below detection (lower limit, 20–50 copies of HIV RNA/mL depending on manufacturer) by cART, there is a continual low level of virus replication. In other human viral infections, with very few exceptions, if the host survives, the virus is completely cleared from the body and a state of immunity against subsequent infection develops. HIV infection very rarely kills the host during primary infection. Certain viruses, such as HSV (Chap. 216), are not completely cleared from the body after infection, but instead enter a latent state; in these cases, clinical latency is accompanied by microbiologic latency. This is not the case with


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InternalMed_Harrison. 216), are not completely cleared from the body after infection, but instead enter a latent state; in these cases, clinical latency is accompanied by microbiologic latency. This is not the case with HIV infection as described above. Chronicity associated with persistent virus replication can also be seen in certain cases of HBV and HCV infections (Chap. 362); however, in these infections the immune system is not a target of the virus.


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InternalMed_Harrison. Escape of HIV from Effective Immune System Control Inherent to the establishment of chronicity of HIV infection is the ability of the virus to evade adequate control and elimination by both the cellular and humoral limbs of the immune system. There are a number of mechanisms whereby the virus accomplishes this evasion. Paramount among these is the establishment of a sustained level of replication associated with the generation of viral diversity via mutation and recombination. The selection of mutants that escape control by CD8+ cytolytic T lymphocytes (CTLs) is critical to the propagation and progression of HIV infection. The high rate of virus replication associated with inevitable mutations also contributes to the inability of antibody to neutralize the autologous virus and thus to contain the virus quasispecies present in an individual at any given time. Extensive analyses of sequential HIV isolates and host responses have demonstrated that viral escape from B cell and CD8+ T cell


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InternalMed_Harrison. the virus quasispecies present in an individual at any given time. Extensive analyses of sequential HIV isolates and host responses have demonstrated that viral escape from B cell and CD8+ T cell epitopes occurs early after infection and allows the virus to stay one step ahead of effective immune responses. Virus-specific CD8+ CTLs expand greatly during primary HIV infection, and likely represent the high-affinity responses that would be expected to be most efficient in eliminating virus-infected cells; however, the restriction is generally incomplete as viral replication persists at relatively high levels in the majority of individuals. In addition to viral escape from CTLs through high rates of mutation, it is thought that the initially strong response becomes qualitatively dysfunctional owing to the overwhelming immune activation resulting from persistent viral replication, similar to the exhaustion of CD8+ CTLs that has been reported in the murine model of lymphocytic


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InternalMed_Harrison. dysfunctional owing to the overwhelming immune activation resulting from persistent viral replication, similar to the exhaustion of CD8+ CTLs that has been reported in the murine model of lymphocytic choriomeningitis virus (LCMV) infection. Several studies have indicated that exhaustion of HIV-specific CD8+ T cells during prolonged immune activation is associated with expression of inhibitory receptors, such


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InternalMed_Harrison. CHAPTER 226 Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1230 as programmed death (PD) 1 molecule (of the B7-CD28 family of molecules), as well as loss of polyreactivity and proliferative capacity. Another mechanism contributing to the evasion by HIV of immune system control is the downregulation of HLA class I molecules on the surface of HIV-infected cells by the viral proteins Nef, Tat, and Vpu, resulting in the lack of ability of the CD8+ CTL to recognize and kill the infected target cell. Although this downregulation of HLA class I molecules would favor elimination of HIV-infected cells by natural killer (NK) cells, this latter mechanism does not seem to remove HIV-infected cells effectively (see below). The principal targets of neutralizing antibodies against HIV are the envelope proteins gp120 and gp41. HIV employs at least three mechanisms to evade neutralizing responses: hypervariability in the primary sequence of the envelope, extensive glycosylation of


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InternalMed_Harrison. are the envelope proteins gp120 and gp41. HIV employs at least three mechanisms to evade neutralizing responses: hypervariability in the primary sequence of the envelope, extensive glycosylation of the envelope, and conformational masking of neutralizing epitopes. Several studies that have followed the humoral immune response to HIV from the earliest points after primary infection indicate that the virus continually mutates to escape the emerging antibody response such that the sequential antibodies that are induced do not neutralize the autologous virus. Broadly neutralizing antibodies capable of neutralizing a wide range of primary HIV isolates in vitro occur in only about 20% of HIV-infected individuals, and, when they do occur, it generally requires 2 to 3 years of infection with continual virus replication to drive the affinity maturation of the antibodies. Unfortunately, by the time these broadly neutralizing antibodies are formed, they are ineffective in containing the virus


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InternalMed_Harrison. virus replication to drive the affinity maturation of the antibodies. Unfortunately, by the time these broadly neutralizing antibodies are formed, they are ineffective in containing the virus replication in the patient. Persistent viremia also results in exhaustion of B cells similar to the exhaustion reported for CD4+ T cells, adding to the defects in the humoral response to HIV. CD4+ T cell help is essential for the integrity of antigen-specific immune responses, both humoral and cell-mediated. HIV preferentially infects activated CD4+ T cells including HIV-specific CD4+ T cells, and so this loss of viral-specific helper T cell responses has profound negative consequences for the immunologic control of HIV replication. Furthermore, this loss occurs early in the course of infection, and animal studies indicate that 40–70% of all memory CD4+ T cells in the GALT are eliminated during acute infection. Another potential means of escape of HIV-infected cells from elimination by CD8+ CTLs


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InternalMed_Harrison. animal studies indicate that 40–70% of all memory CD4+ T cells in the GALT are eliminated during acute infection. Another potential means of escape of HIV-infected cells from elimination by CD8+ CTLs is the sequestration of infected cells in immunologically privileged sites such as the central nervous system (CNS). Finally, the escape of HIV from immune-mediated elimination during primary infection allows the formation of a pool of latently infected cells that may not be recognized or completely eliminated by virus-specific CTLs or by ART (see below). Thus, despite a potent immune response and the marked downregulation of virus replication following primary HIV infection, HIV succeeds in establishing a state of chronic infection with a variable degree of persistent virus replication. During this period most patients make the clinical transition from acute primary infection to variable periods of clinical latency or smoldering disease activity (see below).


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InternalMed_Harrison. The HIV Reservoir: Obstacles to the Eradication of Virus A pool of latently infected, resting CD4+ T cells that serves as at least one component of the persistent reservoir of virus exists in virtually all HIV-infected individuals, including those who are receiving cART. Such cells carry an integrated form of HIV DNA in the genome of the host and can remain in this state until an activation signal drives the expression of HIV transcripts and ultimately replication-competent virus. This form of latency is to be distinguished from preintegration latency, in which HIV enters a resting CD4+ T cell and, in the absence of an activation signal, reverse transcription of the HIV genome occurs to a certain extent but the resulting proviral DNA fails to integrate into the host genome. This period of preintegration latency may last hours to days, and if no activation signal is delivered to the cell, the proviral DNA loses its capacity to initiate a productive infection. If these cells do become


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InternalMed_Harrison. preintegration latency may last hours to days, and if no activation signal is delivered to the cell, the proviral DNA loses its capacity to initiate a productive infection. If these cells do become activated prior to decay of the preintegration complex, reverse transcription proceeds to completion and the virus continues along its replication cycle (see above and Fig. 226-20). The pool of cells that are in the postintegration state of latency is established early during the


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InternalMed_Harrison. T cell activation (Ag, cytokines) Degradation of unintegrated HIV DNA T cell activation (Ag, cytokines) effect of Resting latently infected virus CD4+ memory T cells T cell activation (Ag, cytokines)


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InternalMed_Harrison. FIGuRE 226-20 Generation of latently infected, resting CD4+ T cells in HIV-infected individuals. See text for details. Ag, antigen; CTLs, cytolytic T lymphocytes. (Courtesy of TW Chun; with permission.) course of primary HIV infection. Despite the suppression of plasma viremia to <50 copies of HIV RNA per milliliter by potent regimens of cART administered over several years, this pool of latently infected cells persists and can give rise to replication-competent virus upon cellular activation. Modeling studies built on projections of decay curves have estimated that in such a setting of prolonged suppression, it would require a few to several years for the pool of latently infected cells to be completely eliminated. This has not been documented to occur spontaneously in any patients very likely because the latent viral reservoir is continually replenished by the low levels of persistent virus replication that may remain below the limits of detection of current assays (see below) (Fig.


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InternalMed_Harrison. because the latent viral reservoir is continually replenished by the low levels of persistent virus replication that may remain below the limits of detection of current assays (see below) (Fig. 226-20), even in patients who for the most part are treated successfully. Reservoirs of HIV-infected cells, latent or otherwise, can exist in a number of compartments including the lymphoid tissue, peripheral blood, and the CNS (likely in cells of the monocyte/ macrophage lineage) as well as in other unidentified locations. Over the past several years attempts have been made to eliminate HIV in the latent viral reservoir using agents that stimulate resting CD4+ T cells during the course of cART; however, such attempts have been unsuccessful. Thus, this persistent reservoir of infected cells and/or low levels of persistent virus replication are major obstacles to the goal of eradication of virus from infected individuals and hence a “cure,” despite the favorable clinical outcomes that have


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InternalMed_Harrison. low levels of persistent virus replication are major obstacles to the goal of eradication of virus from infected individuals and hence a “cure,” despite the favorable clinical outcomes that have resulted from cART.


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InternalMed_Harrison. Viral Dynamics The dynamics of viral production and turnover have been quantified using mathematical modeling in the setting of the administration of reverse transcriptase and protease inhibitors to HIV-infected individuals in clinical studies. Treatment with these drugs resulted in a precipitous decline in the level of plasma viremia, which typically fell by well over 90% within 2 weeks. The number of CD4+ T cells in the blood increased concurrently, which suggested that the Productively infected Latently infected per milliliter in the absence of therapy, there is virtually 1231 CD4+ lymphocytes CD4+ lymphocytes always some degree of ongoing virus replication. t1/2 = 1.0 day Uninfected, activated Long-lived


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InternalMed_Harrison. t1/2 = 1.0 day Uninfected, activated Long-lived In untreated patients or in patients in whom therapy has not adequately controlled virus replication, after a variable period, usually measured in years, the CD4+ T cell count falls below a critical level (<200/μL) and the patient becomes highly susceptible to opportunistic disease (Fig. 226-17). For this reason, the CDC case definition of AIDS includes all HIV-infected individuals over 5 years of age with CD4+ T cell counts below this level (Table 226-2). Patients may experience constitutional signs and symptoms or may develop an opportunistic disease abruptly without any prior symptoms, although the latter scenario is unusual. The depletion of CD4+ T cells continues to be progressive and unrelenting in this phase. It is not CD4+ lymphocytes infected with defective viruses


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InternalMed_Harrison. FIGuRE 226-21 Dynamics of HIV infection in vivo. See text for detailed description. (From AS Perelson et al: Science 271:1582, 1996.) killing of CD4+ T cells was linked directly to the levels of replicating virus. However, a significant component of the early rise in CD4+ T cell numbers following the initiation of therapy may be due to the redistribution of cells into the peripheral blood from other tissue compartments throughout the body as a consequence of therapy-related diminution in viremia-associated immune system activation. It was determined on the basis of modeling the kinetics of viral decline and the emergence of resistant mutants during therapy that 93–99% of the circulating virus originated from recently infected, rapidly turning over CD4+ T cells and that ~1–7% of circulating virus originated from longer-lived cells, likely monocytes/macrophages. A negligible amount of circulating virus originated from the pool of latently infected cells (Fig. 226-21). It was also


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InternalMed_Harrison. virus originated from longer-lived cells, likely monocytes/macrophages. A negligible amount of circulating virus originated from the pool of latently infected cells (Fig. 226-21). It was also determined that the half-life of a circulating virion was ~30–60 min and that of productively infected cells was 1 day. Given the relatively steady level of plasma viremia and of infected cells, it appears that extremely large amounts of virus (~1010–1011 virions) are produced and cleared from the circulation each day. In addition, data suggest that the minimal duration of the HIV-1 replication cycle in vivo is ~2 days. Other studies have demonstrated that the decrease in plasma viremia that results from cART correlates closely with a decrease in virus replication in lymph nodes, further confirming that lymphoid tissue is the main site of HIV replication and the main source of plasma viremia.


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InternalMed_Harrison. The level of steady-state viremia, called the viral set point, at ~1 year following acquisition of HIV infection has important uncommon for CD4+ T cell counts in the untreated patient to drop to as low as 10/μL or even to zero. In for opportunistic infections are readily accessible to such patients, survival is increased dramatically even in those patients with advanced HIV disease. In contrast, untreated patients who progress to this severest form of immunodeficiency usually succumb to opportunistic infections or neoplasms (see below).


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InternalMed_Harrison. It is important to distinguish between the terms long-term survivor and long-term nonprogressor. Long-term nonprogressors are by definition long-term survivors; however, the reverse is not always true. Predictions from one study that antedated the availability of effective cART estimated that ~13% of homosexual/bisexual men who were infected at an early age may remain free of clinical AIDS for >20 years. Many of these individuals may have progressed in their degree of immune deficiency; however, they certainly survived for a considerable period of time. With the advent of effective cART, the survival of HIV-infected individuals has dramatically increased. Early in the AIDS epidemic, prior to the availability of therapy, if a patient presented with a life-threatening opportunistic infection, the median survival was 26 weeks from the time of presentation. Currently, an HIV-infected 20-year-old individual in a high-income country who is appropriately treated with cART can expect to live


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InternalMed_Harrison. the median survival was 26 weeks from the time of presentation. Currently, an HIV-infected 20-year-old individual in a high-income country who is appropriately treated with cART can expect to live at least 50 years according to mathematical model projections. In the face of cART, long-term survival is becoming commonplace. Definitions of


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders prognostic implications for the progression of HIV disease 1 in the untreated patient. It has been demonstrated that as a group untreated HIV-infected individuals who have a low 0.9 HIV RNA copies/mL ˜9060 9,061 to 26,040 26,041 to 72,540 >72,540 set point at 6 months to 1 year following infection progress is very high at that time (Fig. 226-22). Clinical Latency versus Microbiologic Latency With the excep tion of long-term nonprogressors (see “Long-Term Survivors and Long-Term Nonprogressors,” below), the level of CD4+


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InternalMed_Harrison. Clinical Latency versus Microbiologic Latency With the excep tion of long-term nonprogressors (see “Long-Term Survivors and Long-Term Nonprogressors,” below), the level of CD4+ T cells in the blood decreases progressively in HIV-infected individuals in the absence of cART. The decline in CD4+ T cells may be gradual or abrupt, the latter usually reflecting a significant spike in the level of plasma viremia. Most patients 0.8 0.7 0.6 0.5 0.4 0.3 0.2 are relatively asymptomatic while this progressive decline is 0.1 taking place (see below) and are often described as being in a state of clinical latency. However, this term is misleading; it 0 does not mean disease latency, since progression, although slow in many cases, is generally relentless during this period. Time, years


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InternalMed_Harrison. Furthermore, clinical latency should not be confused with FIGuRE 226-22 Relationship between levels of virus and rates of disease microbiologic latency, since varying levels of virus replica-progression. Kaplan-Meier curves for AIDS-free survival stratified by basetion inevitably occur during this period of clinical latency. line HIV-1 RNA categories (copies per milliliter). (From JW Mellors et al: Science Even in those rare patients who have <50 copies of HIV RNA 272:1167, 1996.) 1232 long-term nonprogressors have varied considerably over the years, and so such individuals constitute a heterogeneous group. Long-term nonprogressors were first described in the 1990s. Originally, individuals were considered to be long-term nonprogressors if they had been infected with HIV for a long period (≥10 years), their CD4+ T cell counts were in the normal range, and they remained stable over years without receiving cART. Approximately 5–15% of HIV-infected individuals fell into this broader


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InternalMed_Harrison. (≥10 years), their CD4+ T cell counts were in the normal range, and they remained stable over years without receiving cART. Approximately 5–15% of HIV-infected individuals fell into this broader nonprogressor category. However, this group was rather heterogenous and over time a significant proportion of these individuals progressed and ultimately required therapy. From this broader group, a much smaller subgroup of “elite” controllers or nonprogressors was identified, and they constituted less than 1% of HIV-infected individuals. These elite controllers, by definition, have extremely low levels of plasma viremia and normal CD4+ T cell counts. It is noteworthy that certain of their HIV-specific immune responses are robust and clearly superior to those of HIV-infected progressors. In this group of elite controllers certain HLA class I haplotypes are overrepresented, particularly HLA-B57-01 and HLA-B27-05. Outside of the subgroup of elite controllers, a number of other genetic factors


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InternalMed_Harrison. group of elite controllers certain HLA class I haplotypes are overrepresented, particularly HLA-B57-01 and HLA-B27-05. Outside of the subgroup of elite controllers, a number of other genetic factors have been shown to be involved to a greater or lesser degree in the control of virus replication and thus in the rate of HIV disease progression (see “Genetic Factors in HIV-1 and AIDS Pathogenesis,” below).


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InternalMed_Harrison. Regardless of the portal of entry of HIV, lymphoid tissues are the major anatomic sites for the establishment and propagation of HIV infection. Despite the use of measurements of plasma viremia to determine the level of disease activity, virus replication occurs mainly in lymphoid tissue and not in blood; indeed, the level of plasma viremia directly reflects virus production in lymphoid tissue. Some patients experience progressive generalized lymphadenopathy early in the course of the infection; others experience varying degrees of transient lymphadenopathy. Lymphadenopathy reflects the cellular activation and immune response to the virus in the lymphoid tissue, which is generally characterized by follicular or germinal center hyperplasia. Lymphoid tissue involvement is a common denominator of virtually all patients with HIV infection, even those without easily detectable lymphadenopathy.


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InternalMed_Harrison. Simultaneous examinations of lymph tissue and peripheral blood in patients and monkeys during various stages of HIV and SIV infection, respectively, have led to substantial insight into the pathogenesis of HIV disease. In most of the original human studies, peripheral lymph nodes have been used predominantly as the source of lymphoid tissue. More recent studies in monkeys and humans have also focused on the GALT, where the earliest burst of virus replication occurs associated with marked depletion of CD4+ T cells. In detailed studies of peripheral lymph node tissue, using a combination of polymerase chain reaction (PCR) techniques for HIV DNA and HIV RNA in tissue and HIV RNA in plasma, in situ hybridization for HIV RNA, and light and electron microscopy, the following picture has emerged. During acute HIV infection resulting from mucosal transmission, virus replication progressively amplifies from scattered lymphoid cells in the lamina propria to draining lymphoid tissue, leading to


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InternalMed_Harrison. During acute HIV infection resulting from mucosal transmission, virus replication progressively amplifies from scattered lymphoid cells in the lamina propria to draining lymphoid tissue, leading to high levels of plasma viremia. The GALT plays a major role in the amplification of virus replication, and virus is disseminated from replication in the GALT to peripheral lymphoid tissue. A profound degree of cellular activation occurs (see below) and is reflected in follicular or germinal center hyperplasia. At this time copious amounts of extracellular virions (both infectious and defective) are trapped on the processes of the follicular dendritic cells (FDCs) in the germinal centers of the lymph nodes. Virions that have bound complement components on their surfaces attach to the surface of FDCs via interactions with complement receptors and likely via Fc receptors that bind to antibodies that are attached to the virions. In situ hybridization reveals expression of virus in individual


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InternalMed_Harrison. FDCs via interactions with complement receptors and likely via Fc receptors that bind to antibodies that are attached to the virions. In situ hybridization reveals expression of virus in individual cells of the paracortical area and, to a lesser extent, the germinal center (Fig. 226-23). The persistence of trapped virus after the transition from acute to chronic infection likely reflects a steady state whereby trapped virus turns over and is replaced by fresh virions that are continually produced. The trapped virus, either as whole virion or shed envelope, serves as a continual activator of CD4+ T cells, thus driving further virus replication.


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InternalMed_Harrison. FIGuRE 226-23 HIV in the lymph node of an HIV-infected indi-vidual. An individual cell infected with HIV shown expressing HIV RNA by in situ hybridization using a radiolabeled molecular probe. Original ×500. (Adapted from G Pantaleo, AS Fauci et al: Nature 362:355, 1993.)


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InternalMed_Harrison. During early and chronic/asymptomatic stages of HIV disease, the architecture of lymphoid tissues is generally preserved and may even be hyperplastic owing to an increased presence of B cells and specialized CD4+ T cells called follicular helper CD4+ T cells (TFH) in prominent germinal centers. Extracellular virions can be seen by electron microscopy attached to FDC processes. The trapping of antigen is a physiologically normal function for the FDCs, which present antigen to B cells and, along with the action of TFH cells, contribute to the generation of B cell memory. However, in the case of HIV, persistent cellular activation, resulting in the secretion of proinflammatory cytokines such as interleukin (IL) 1β, tumor necrosis factor (TNF) α, IFN-γ, and IL-6, which can induce viral replication (see below) and diminish the effectiveness of the immune response against the virus. In addition, the CD4+ TFH cells that are recruited into the germinal center to provide help to B cells in the


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InternalMed_Harrison. (see below) and diminish the effectiveness of the immune response against the virus. In addition, the CD4+ TFH cells that are recruited into the germinal center to provide help to B cells in the generation of an HIV-specific immune response are highly susceptible to infection by virus either trapped on FDC or propagated locally. Thus, in HIV infection, a normal physiologic function of the immune system that contributes to the clearance of virus, as well as to the generation of a specific immune response, can also have deleterious consequences.


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InternalMed_Harrison. As the disease progresses, the architecture of lymphoid tissues begins to show disruption. Confocal microscopy reveals destruction of the fibroblastic reticular cell (FRC) and FDC networks in the T cell zone and B cell follicles, respectively, and an incapacity to replenish naïve cells. The mechanisms of destruction are not completely understood, but they are thought to be associated with collagen deposition causing fibrosis and loss of production of cytokines such as IL-7 and lymphotoxin-α, which are critical to the maintenance of lymphoid tissues and their lymphocyte constituents. As the disease progresses to an advanced stage, there is complete disruption of the architecture of the lymphoid tissues, accompanied by dissolution of the FRC and FDC networks. At this point, the lymph nodes are “burnt out.” This destruction of lymphoid tissue compounds the immunodeficiency of HIV disease and contributes both to the inability to control HIV replication (leading usually to high levels of


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InternalMed_Harrison. are “burnt out.” This destruction of lymphoid tissue compounds the immunodeficiency of HIV disease and contributes both to the inability to control HIV replication (leading usually to high levels of plasma viremia in the untreated or inadequately treated patient) and to the inability to mount adequate immune responses against opportunistic pathogens. The events from primary infection to the ultimate destruction of the immune system are illustrated in Fig. 226-24. Recently, nonhuman primate studies and some human studies have examined GALT at various stages of HIV disease. Within the GALT, the basal level of activation combined with virus-mediated cellular activation results in the infection and elimination of an estimated 50–90% of CD4+ T cells in the gut. The extent of viremia are suppressed to below the level 1233 of detection by standard assays. From a virologic standpoint, although quiescent CD4+ T cells can be infected with Massive viremia


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InternalMed_Harrison. HIV, reverse transcription, integration, and virus spread are much more efficient in activated cells. Furthermore, cellular activation induces expression Wide dissemination to lymphoid organs of virus in cells latently infected with HIV. In essence, immune activation and Trapping of virus and inflammation provide the engine that establishment of chronic, drives HIV replication. In addition to endogenous factors such as cytokines, Partial immunologic a number of exogenous factors such control of virus replication as other microbes that are associated


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InternalMed_Harrison. Destruction of have important effects on HIV pathogen-envelope-mediated esis. Co-infection in vivo or in vitro with a range of viruses, such as HSV types 1 and 2, cytomegalovirus (CMV), human herpesvirus (HHV) 6, Epstein-Barr virus FIGuRE 226-24 Events that transpire from primary HIV infection through the establishment of (EBV), HBV, adenovirus, and HTLV-1 chronic persistent infection to the ultimate destruction of the immune system. See text for details. have been shown to upregulate HIV CTLs, cytolytic T lymphocytes; GALT, gut-associated lymphoid tissue. this early damage to GALT, which constitutes a major component of lymphoid tissue in the body, may play a role in determining the potential for immunologic recovery of the memory cell subset. IMMuNE ACTIVATION, INFLAMMATION, AND HIV PATHOGENESIS


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InternalMed_Harrison. IMMuNE ACTIVATION, INFLAMMATION, AND HIV PATHOGENESIS Activation of the immune system and variable degrees of inflammation are essential components of any appropriate immune response to a foreign antigen. However, immune activation and inflammation, which can be considered aberrant in HIV-infected individuals, play a critical role in the pathogenesis of HIV disease and other chronic conditions associated with HIV disease. Immune activation and inflammation in the HIV-infected individual contribute substantially to (1) the replication of HIV, (2) the induction of immune dysfunction, and (3) the increased incidence of chronic conditions associated with persistent immune activation and inflammation (Table 226-4).


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InternalMed_Harrison. indUction of Hiv replication by aberrant immUne activation The immune system is normally in a state of homeostasis, awaiting perturbation by foreign antigenic stimuli. Once the immune response deals with and clears the antigen, the system returns to relative quiescence (Chap. 372e). This is generally not the case in HIV infection where, in the untreated patient, virus replication is invariably persistent with very few exceptions and immune activation is persistent. HIV replicates most efficiently in activated CD4+ T cells; in HIV infection, chronic activation provides the cell substrates necessary for persistent virus replication throughout the course of HIV disease, particularly in the untreated patient and to variable degrees even in certain patients receiving cART whose levels of plasma expression. In addition, infestation with nematodes has been shown to be associ ated with a heightened state of immune activation that facilitates HIV replication; in certain studies deworming of


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InternalMed_Harrison. expression. In addition, infestation with nematodes has been shown to be associ ated with a heightened state of immune activation that facilitates HIV replication; in certain studies deworming of the infected host has resulted in a decrease in plasma viremia. Two diseases of extraordinary global health significance, malaria and tuberculosis (TB), have been shown to increase HIV viral load in dually infected individuals. Globally, Mycobacterium tuberculosis is the most common opportunistic infection in HIV-infected individuals (Chap. 202). In addition to the fact that HIV-infected individuals are more likely to develop active TB after exposure, it has been demonstrated that active TB can accelerate the course of HIV infection. It has also been shown that levels of plasma viremia are greatly elevated in HIV-infected individuals with active TB who are not on cART, compared with pre-TB levels and levels of viremia after successful treatment of the active TB. The situation is similar in


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InternalMed_Harrison. elevated in HIV-infected individuals with active TB who are not on cART, compared with pre-TB levels and levels of viremia after successful treatment of the active TB. The situation is similar in the interaction between HIV and malaria parasites (Chap. 248). Acute infection of HIV-infected individuals with Plasmodium falciparum increases HIV viral load, and the increased viral load is reversed by effective malaria treatment.


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InternalMed_Harrison. microbial translocation and persistent immUne activation One proposed mechanism of persistent immune activation involves the disruption of the mucosal barrier in the gut due to HIV replication in and disruption of submucosal lymphoid tissue. As a result of this disruption, there is an increase in the products, particularly lipopolysaccharide (LPS), of bacteria that translocate from the bowel lumen through the damaged mucosa to the circulation, leading to persistent systemic immune activation and inflammation. This effect can persist even after the HIV viral load is brought to <50 copies/mL by cART. Depletion in the GALT of IL-17–producing T cells, which are responsible for defense against extracellular bacteria and fungi, also is thought to contribute to HIV pathogenesis.


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InternalMed_Harrison. persistent immUne activation and inflammation indUce immUne dysfUnction The activated state in HIV infection is reflected by hyperactivation of B cells leading to hypergammaglobulinemia; increased lymphocyte turnover; activation of monocytes; expression of activation markers on CD4+ and CD8+ T cells; increased activation-associated cellular apoptosis; lymph node hyperplasia, particularly early in the course of disease; increased secretion of proinflammatory cytokines, particularly IL-6; elevated levels of high-sensitivity C-reactive protein, fibrinogen, d-dimer, neopterin, β2-microglobulin, acid-labile interferon, soluble (s) IL-2 receptors (R), sTNFR, sCD27, and sCD40L; and autoimmune phenomena (see “Autoimmune Phenomena,” below). Even in the absence of direct infection of a target cell, HIV envelope proteins can interact


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1234 with cellular receptors (CD4 molecules and chemokine receptors) to deliver potent activation signals resulting in calcium flux, the phosphorylation of certain proteins involved in signal transduction, co-localization of cytoplasmic proteins including those involved in cell trafficking, immune dysfunction, and, under certain circumstances, apoptosis. From an immunologic standpoint, chronic exposure of the immune system to a particular antigen over an extended period may ultimately lead to an inability to sustain an adequate immune response to the antigen in question. In many chronic viral infections, including HIV infection, persistent viremia is associated with “functional exhaustion” of virus-specific T cells, decreasing their capacity to proliferate and perform effector functions. It has been demonstrated that this phenomenon may be mediated, at least in part, by the upregulation of inhibitory receptors on


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InternalMed_Harrison. their capacity to proliferate and perform effector functions. It has been demonstrated that this phenomenon may be mediated, at least in part, by the upregulation of inhibitory receptors on HIV-specific T cells, such as PD-1 shared by both CD4+ and CD8+ T cells, as well as CTLA-4 on CD4+ and Tim-3, 2B4, and CD106 on CD8+ T cells. Furthermore, the ability of the immune system to respond to a broad spectrum of antigens may be compromised if immunocompetent cells are maintained in a state of chronic activation. The deleterious effects of chronic immune activation on the progression of HIV disease are well established. As in most conditions of persistent antigen exposure, the host must maintain sufficient activation of antigen (HIV)-specific responses but must also prevent excessive activation and potential immune-mediated damage to tissues. Certain studies suggest that normal immunosuppressive mechanisms that act to keep hyperimmune activation in check, particularly CD4+, FoxP3+, CD25+


InternalMed_Harrison

InternalMed_Harrison. and potential immune-mediated damage to tissues. Certain studies suggest that normal immunosuppressive mechanisms that act to keep hyperimmune activation in check, particularly CD4+, FoxP3+, CD25+ regulatory T cells (T-regs), may be dysfunctional or depleted in the context of advanced HIV disease.


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InternalMed_Harrison. medical conditions associated witH persistent immUne activation and inflammation in Hiv disease It has become clear, as the survival of HIV-infected individuals has increased, that a number of previously unrecognized medical complications are associated with HIV disease—and that these complications relate to chronic immune activation and inflammation (Table 226-4). These complications can appear even after patients have experienced years of adequate control of viral replication (plasma viremia below detectable levels) for several years. Of particular note are endothelial cell dysfunction and its relationship to cardiovascular disease. Other chronic conditions that have been reported include bone fragility, certain cancers, persistent immune dysfunction, diabetes, kidney and liver disease, and neurocognitive dysfunction, thus presenting an overall picture of accelerated aging.