Immunology_Janeway

Immunology_Janeway. Evidence shows that in addition to being a major target for HIV infection, CD4 T cells also have an important role in the host response to HIVinfected cells. Fig. 13.34 The immune response to HIV. infectious virus is present at relatively low levels in the peripheral blood of infected individuals during a prolonged asymptomatic phase, during which the virus is replicated persistently in lymphoid tissues. During this period, CD4 t-cell counts gradually decline (see Fig. 13.33), although antibodies and CD8 cytotoxic t cells directed against the virus remain at high levels. two different antibody responses are shown in the figure, one to the envelope protein (env) of HiV, and one to the core protein p24. eventually, the levels of antibody and HiV-specific cytotoxic t lymphocytes (Ctls) also decline, and there is a progressive increase in infectious HiV in the peripheral blood.


Immunology_Janeway

Immunology_Janeway. An inverse correlation is found between the strength of CD4 Tcell proliferative responses to HIV antigen and viral load. In addition, the type of effector CD4 Tcell response mounted against the virus appears important. There is an inverse correlation with viral load and control of acute infection in patients whose CD4 T cells express greater TH1 type activity, including production of IFNγ and granzyme B. Moreover, CD4 T cells from patients who do not progress to AIDS long after infection by HIV show strong antiviral proliferative responses. Finally, early treatment of acutely infected individuals with antiretroviral drugs is associated with a recovery in CD4 proliferative responses to HIV antigens. If antiretroviral therapy is stopped, the CD4 responses persist in some of these people and are associated with reduced levels of viremia. However, infection continues to persist in these patients and immunological control of the infection will ultimately fail. If CD4 Tcell responses are


Immunology_Janeway

Immunology_Janeway. are associated with reduced levels of viremia. However, infection continues to persist in these patients and immunological control of the infection will ultimately fail. If CD4 Tcell responses are essential for the control of HIV infection, then the fact that HIV is tropic for these cells and kills them may explain the inability of the host immune response to control the infection in the long term.


Immunology_Janeway

Immunology_Janeway. Antibodies against HIV proteins are generated early in the course of infection, but, like T cells, are ultimately unable to clear the virus. As for viral Tcell epitopes, the virus shows a high capacity for generating escape mutants under the selective pressure of the antibody response. Two aspects of the antibody response appear to be important: (1) generating neutralizing antibodies against gp120 and gp41 envelope viral antigens in order to block viral attachment or entry into CD4positive target cells, and (2) generating nonneutralizing antibodies that target infected cells for antibodydependent cellular cytotoxicity (ADCC). Although neutralizing antibodies are eventually produced in nearly all who are HIVinfected, the relative inaccessibility of viral epitopes that bind CD4 and chemokine coreceptors hampers the development of such antibodies for a prolonged period (typically months); this buys the virus time to generate escape mutants before the neutralizing antibodies can be


Immunology_Janeway

Immunology_Janeway. coreceptors hampers the development of such antibodies for a prolonged period (typically months); this buys the virus time to generate escape mutants before the neutralizing antibodies can be produced. Indeed, the generation of socalled broadly neutralizing antibodies, which can block infection by multiple viral strains, is typically found in those with high viral titers, emphasizing the fact that these antibodies cannot significantly modify established disease. Analyses of effective neutralizing antibodies to HIV indicate that they have undergone extensive somatic hypermutation that is rarely induced before the first year following infection. Nevertheless, the passive administration of some antibodies against HIV can protect experimental animals from mucosal infection by HIV, offering hope that an effective vaccine might be developed that could prevent new infections.


Immunology_Janeway

Immunology_Janeway. In contrast to neutralizing antibodies, which develop late in infection and appear to play a modest role in restraining viral replication, there is growing evidence that nonneutralizing antibodies that recruit ADCC by NK cells, macrophages, and neutrophils develop early in infections and are important in restraining viral replication in concert with the actions of cytolytic CD8 T cells. Again, however, the high rate of mutability of the virus allows it to stay a step ahead and persist. The mutations that occur as HIV replicates can allow resulting virus variants to escape recognition by CTLs or antibodies, and are important in contributing to the longterm failure of the immune system to contain the infection. An immune response is often dominated by T or B cells specific for particular epitopes—immunodominant epitopes—and mutations in immunodominant HIV peptides presented by MHC class I molecules have been found, as have mutations in the epitopes targeted by neutralizing and


Immunology_Janeway

Immunology_Janeway. epitopes—immunodominant epitopes—and mutations in immunodominant HIV peptides presented by MHC class I molecules have been found, as have mutations in the epitopes targeted by neutralizing and nonneutralizing antibodies. Mutant peptides have been found to inhibit T cells responsive to the wildtype epitope, thus allowing both the mutant and wildtype viruses to survive.


Immunology_Janeway

Immunology_Janeway. While the immune response to HIV is ultimately unsuccessful, its importance in restraining disease progression is clear. This is perhaps best exemplified in the tragic case of children infected with HIV perinatally, in whom the course of disease is much more fulminant than in adults. This reflects a poor immune response to the virus in the acute phase of infection due to immaturity of the neonatal immune system, as well as infection by a viral strain that has already evaded an immune system that is genetically close to that of the child. In essence, the poor immune response results in the lack of a latent phase, leading rapidly to AIDS. 13-32 Lymphoid tissue is the major reservoir of HIV infection.


Immunology_Janeway

Immunology_Janeway. In view of the active, ongoing immune response to HIV infections and the advent of antiretroviral therapies that efficiently blunt viral replication (see Section 1335), it is important to identify the reservoirs that allow the virus to persist. Although HIV load and turnover are usually measured in terms of the RNA present in virions in the blood, the major reservoir of HIV infection appears to be lymphoid tissue. Here, in addition to infected CD4 T cells, macrophages, and dendritic cells, HIV is also trapped in the form of immune complexes on the surface of follicular dendritic cells in germinal centers. These cells are not themselves infected but may act as a reservoir of infective virions that can persist for months, if not longer. Although tissue macrophages and dendritic cells seem able to harbor replicating HIV without being killed by it, these cells are shortlived and are not thought to be major reservoirs of latent infection. However, they appear to be important in spreading


Immunology_Janeway

Immunology_Janeway. able to harbor replicating HIV without being killed by it, these cells are shortlived and are not thought to be major reservoirs of latent infection. However, they appear to be important in spreading virus to other tissues, such as the brain, where infected cells in the central nervous system may contribute to the virus’s longterm persistence.


Immunology_Janeway

Immunology_Janeway. From studies of patients receiving antiretroviral treatment, it is estimated that more than 95% of the virus that can be detected in the plasma is derived from productively infected CD4 T cells that have a very short halflife—about 2 days. Virusproducing CD4 T cells are found in the Tcell areas of lymphoid tissues, and these T cells are thought to succumb to infection while being activated in an immune response. Latently infected CD4 memory T cells that become reactivated by antigen also produce virus that can spread to other activated CD4 T cells. In addition to cells that are productively or latently infected, a further large population of cells is infected by defective proviruses, which do not produce infectious virus. Unfortunately, latently infected CD4 memory T cells have an extremely long mean halflife of around 44 months. This means that drug therapy that effectively eliminates viral replication would have to be administered for over 70 years to completely clear the virus.


Immunology_Janeway

Immunology_Janeway. long mean halflife of around 44 months. This means that drug therapy that effectively eliminates viral replication would have to be administered for over 70 years to completely clear the virus. Practically, then, infected patients will never be able to eliminate an HIV infection, and require treatment for life.


Immunology_Janeway

Immunology_Janeway. 13-33 Genetic variation in the host can alter the rate of disease progression.


Immunology_Janeway

Immunology_Janeway. It became clear early in the HIV/AIDS pandemic that the course of the disease could vary widely. Indeed, while nearly all untreated HIVinfected individuals progress to AIDS and ultimately die from opportunistic infections or cancer, not all do. A small percentage of people exposed to the virus seroconvert, but do not seem to have progressive disease. Their CD4 Tcell counts and other measures of immune competence are maintained for decades without antiretroviral therapy. Among these longterm nonprogressors, one subgroup, called elite controllers, have unusually low levels of circulating virus (undetectable by standard clinical assays, despite ongoing lowlevel viral replication) and represent approximately 1 in 300 infected individuals. They are being studied intensively to discover how they are able to control their infection. A second group consists of individuals who engage in highrisk behaviors that repeatedly expose them to infection yet remain virus and diseasefree. Although


Immunology_Janeway

Immunology_Janeway. they are able to control their infection. A second group consists of individuals who engage in highrisk behaviors that repeatedly expose them to infection yet remain virus and diseasefree. Although evidence of prior HIV infection has been reported in such individuals, it is unclear whether these individuals were ever truly infected with infectious virus or were exposed to highly attenuated or defective strains unable e, an effect that acts early in progression to aiDS; l, acts late in aiDS progression; ?, plausible mechanism of action with no direct support. From O’Brien, S.J., and nelson, G.W.: Nat. Genet. 36:565–574. Reprinted with permission from Macmillan Publishers ltd. © 2004.


Immunology_Janeway

Immunology_Janeway. to successfully establish infection. In any case, study of these individuals is of considerable interest as it could provide a better understanding of how the host immune response might better control the virus and define what genetic factors might predispose to a protective host response. It might also provide mechanistic insights that could guide development of better vaccines.


Immunology_Janeway

Immunology_Janeway. Although genetic variation in the virus itself can affect the outcome of infection, a growing number of host gene variants are being defined that impact the rate of progression of HIV infection toward AIDS. The implementation of genomewide association studies (GWAS) and, more recently, better highthroughput tools to define individual genetic variation (for example, exome and wholegenome sequencing) are accelerating discovery of genetic variations that distinguish highly susceptible and resistant individuals (Fig. 13.35). As discussed in Section 1330, one of the clearest cases of host genetic variation affecting HIV infection is a mutant allele of CCR5, CCR5Δ32, that when homozygous effectively blocks HIV1 infection, and when heterozygous may slow AIDS progression. Genetic polymorphisms in the HLA class I locus, particularly in HLA-B and HLA-C alleles, are another major factor in determining disease progression and are currently the strongest predictors of HIV control. Evidence from


Immunology_Janeway

Immunology_Janeway. in the HLA class I locus, particularly in HLA-B and HLA-C alleles, are another major factor in determining disease progression and are currently the strongest predictors of HIV control. Evidence from GWAS has mapped polymorphisms to the peptidebinding groove of HLA class I molecules as key determinants defining disease progression. Polymorphisms outside of the peptidebinding groove, as well as those in noncoding regions that control the expression levels of HLA molecules, are also implicated. The HLA class I alleles HLA-B57, HLA-B27, and HLA-B13, among others, are associated with a better prognosis, whereas HLA-B35 and HLA-B07 are associated with more rapid disease progression. Homozygosity of HLA class I alleles (HLA-A, HLA-B, and HLA-C) is also associated with more rapid progression, presumably because the Tcell response to infection is less diverse. Remarkably, one of the strongest associations with viral control is a singlenucleotide polymorphism (SNP) 35 kb upstream of the HLA-C


Immunology_Janeway

Immunology_Janeway. because the Tcell response to infection is less diverse. Remarkably, one of the strongest associations with viral control is a singlenucleotide polymorphism (SNP) 35 kb upstream of the HLA-C locus; this polymorphism confers greater immune control that correlates with increased expression levels of HLAC—with the greater control presumably being due to enhanced presentation of viral peptides to CD8 T cells. Certain polymorphisms of the killercell immunoglobulinlike receptors (KIRs) present on NK cells (see Section 326), in particular the receptor KIR3DS1 in combination with certain alleles of HLA-B, also delay the progression to AIDS. Mutations that affect the production of cytokines such as IFNγ and IL10 have also been implicated in the restriction of HIV progression.


Immunology_Janeway

Immunology_Janeway. Fig. 13.35 Genes that influence progression to AIDS in humans.


Immunology_Janeway

Immunology_Janeway. Effect Mechanism of action Allele ModeGene HIV entry Cytokine anti-HIV Acquired immunity, cell-mediated Acquired immunity, innate Recessive Prevents infection Knockout of CCR5 expression Recessive Accelerates AIDS (E) Increases CCR5 expression CCR5 ˜32 P1 Dominant Delays AIDS Interacts with and reduces CXCR4 I64CCR2 Homozygous Accelerates AIDS Decreases breadth of HLA class I epitope recognition A, B, C Accelerates AIDS Defects CD8-mediated T-cell clearance of HIV-1 B*35-Px HLA Codominant Delays AIDS Delays HIV-1 escape B*27 B*57 Dominant Accelerates AIDS Decreases CCL5 expression In1.1cCCL5 Recessive Delays AIDS (L) Impedes CCR5–CXCR4 transition (?) 3´ACXCL12 Dominant Accelerates P. jirovecii pneumonia (L) Alters T-cell activations (?)E3KCXCR6 Dominant Enhances infection Stimulates immune response (?)H7CCL2-CCL7-CCL11 Dominant Accelerates AIDS (E) –179TIFNG Epistatic with HLA-Bw4 Delays AIDS Clears HIV+, HLA– cells (?) 3DS1KIR3DS1 Dominant Limits infection Decreases IL-10 expression


Immunology_Janeway

Immunology_Janeway. response (?)H7CCL2-CCL7-CCL11 Dominant Accelerates AIDS (E) –179TIFNG Epistatic with HLA-Bw4 Delays AIDS Clears HIV+, HLA– cells (?) 3DS1KIR3DS1 Dominant Limits infection Decreases IL-10 expression 5´AIL10 Accelerates AIDS Dominant Prevents lymphoma (L) Decreases available CCR5 Delays AIDS Genes that infuence progression to AIDS 13-34 The destruction of immune function as a result of HIV infection leads to increased susceptibility to opportunistic infection and eventually to death.


Immunology_Janeway

Immunology_Janeway. When CD4 Tcell numbers decline below a critical level, cellmediated immunity is lost, and infections with a variety of opportunistic microbes appear (Fig. 13.36). Typically, resistance is lost early to oral Candida species and to M. tuberculosis, which cause thrush (oral candidiasis) and tuberculosis, respectively. Later, patients suffer from shingles (caused by the activation of latent herpes zoster), from aggressive EBVinduced Bcell lymphomas, and from Kaposi sarcoma, a tumor of endothelial cells that probably results both from a response to cytokines produced in the infection and a herpesvirus called Kaposi sarcomaassociated herpesvirus (KSHV, or HHV8). Since the earliest recognition of AIDS, pneumonia caused by P. jirovecii (previously called P. carinii) has been the most common opportunistic infection; it was typically fatal before effective antifungal therapy was introduced. Coinfection by hepatitis C virus is common and associated with more rapid progression of hepatitis. In


Immunology_Janeway

Immunology_Janeway. infection; it was typically fatal before effective antifungal therapy was introduced. Coinfection by hepatitis C virus is common and associated with more rapid progression of hepatitis. In the final stages of AIDS, infection with cytomegalovirus or a member of the Mycobacterium avium group of bacteria is more prominent. It is important to note that not all patients with AIDS get all of these infections or tumors, and there are other tumors and infections that are less prominent but still significant. Figure 13.36 lists the most common opportunistic infections and tumors, which are typically controlled until the CD4 Tcell count drops toward zero.


Immunology_Janeway

Immunology_Janeway. infections are the major cause of death in aiDS, the most prominent being respiratory infection with P. jirovecii and mycobacteria. Host defense against most of these pathogens requires effective macrophage activation by CD4 t cells or effective cytotoxic t cells. Opportunistic pathogens are present in the normal environment, but cause severe disease primarily in immunocompromised hosts, such as aiDS patients and cancer patients. aiDS patients are also susceptible to several rare cancers, such as Kaposi sarcoma [associated with human herpesvirus 8 (HHV8)] and various lymphomas, suggesting that immune surveillance of the causative herpesviruses by t cells can normally prevent such tumors (see Chapter 16). 13-35 Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells. Studies with drugs that block HIV replication indicate that the virus is repli cating rapidly at all phases of infection, including the asymptomatic phase.


Immunology_Janeway

Immunology_Janeway. Studies with drugs that block HIV replication indicate that the virus is repli cating rapidly at all phases of infection, including the asymptomatic phase. Three viral proteins in particular have been the target of drugs aimed at arrest ing viral replication. These are viral reverse transcriptase, which is required for synthesis of the provirus; viral integrase, which is required for insertion of the viral provirus into the host genome; and viral protease, which cleaves viral polyproteins to produce virion proteins and viral enzymes. Reverse tran scriptase is inhibited by nucleoside analogs such as zidovudine (AZT), which was the first antiHIV drug to be licensed in the United States. Inhibitors of reverse transcriptase, integrase, and protease prevent infection of uninfected Therapy with antiretroviral drugs (% of patient days)


Immunology_Janeway

Immunology_Janeway. Therapy with antiretroviral drugs (% of patient days) Fig. 13.37 The mortality of patients with advanced HIV infection fell in the United States in parallel with the introduction of combination antiretroviral drug therapy. the graph shows the number of deaths, expressed each calendar quarter as the deaths per 100 person-years. Figure based on data from F. Palella.


Immunology_Janeway

Immunology_Janeway. Fig. 13.38 The time-course of reduction of HIV circulating in the blood during drug treatment. the production of new HiV particles can be arrested for prolonged periods by treatment using combinations of protease inhibitors and viral reversetranscriptase inhibitors. after the initiation of such treatment, virus production is curtailed as the infected cells die and no new cells are infected. the half-life of virus decay occurs in three phases. in the first phase the half-life (t1/2) is about 2 days, reflecting the half-life of productively infected CD4 t cells; this phase lasts about 2 weeks, during which time viral production declines cells; cells that are already infected can continue to produce virions because, once the provirus is established, reverse transcriptase and integrase are not needed to make new virus particles, and while the viral protease acts at a very late maturation step of the virus, inhibition of the protease does not prevent virus from being released. However, in


Immunology_Janeway

Immunology_Janeway. needed to make new virus particles, and while the viral protease acts at a very late maturation step of the virus, inhibition of the protease does not prevent virus from being released. However, in all cases, further cycles of infection by released virions are blocked, and replication is therefore prevented.


Immunology_Janeway

Immunology_Janeway. The introduction of combination therapy with a cocktail of viral protease inhibitors and nucleoside analogs, also known as highly active antiretroviral therapy (HAART), dramatically reduced mortality and morbidity in patients with advanced HIV infection in the United States between 1995 and 1997 (Fig. 13.37). Many patients treated with HAART show a rapid and dramatic reduction in viremia, eventually maintaining levels of HIV RNA close to the limit of detection (50 copies per ml of plasma) for a long period (Fig. 13.38). It is unclear how the virus particles are removed so rapidly from the circulation after the initiation of HAART. It seems most likely that they are opsonized by specific antibody and complement and removed by cells of the mononuclear phagocyte system. Opsonized HIV particles may also be trapped in lymphoid follicles on the surface of follicular dendritic cells.


Immunology_Janeway

Immunology_Janeway. HAART is also accompanied by a slow but steady increase in CD4 T cells, despite the fact that many other compartments of the immune system remain compromised. Three complementary mechanisms have been established for the recovery in CD4 Tcell numbers. The first is a redistribution of CD4 T memory cells from lymphoid tissues into the circulation as viral replication as the lymphocytes that were productively infected at the onset of treatment die. Released virus is rapidly cleared from the circulation, where it has a half-life of 6 hours, and there is a decrease in virus levels in plasma of more than 95% during this first phase. the second phase lasts for about 6 months; the virus now has a half-life of about 2 weeks. During this phase, virus is released from infected macrophages and from resting, latently infected CD4 t cells stimulated to divide and develop productive infection. it is thought that there is then a third phase of unknown length that results from the reactivation of


Immunology_Janeway

Immunology_Janeway. resting, latently infected CD4 t cells stimulated to divide and develop productive infection. it is thought that there is then a third phase of unknown length that results from the reactivation of integrated provirus in memory t cells and other long-lived reservoirs of infection. this reservoir of latently infected cells might remain present for many years. Measurement of this phase of viral decay is impossible at present because viral levels in plasma are below detectable levels (dotted line). Data Months on treatment courtesy of G.M. Shaw.


Immunology_Janeway

Immunology_Janeway. is controlled; this occurs within weeks of starting treatment. The second is a reduction in the abnormal levels of immune activation as HIV infection is controlled; this is associated with reduced killing of infected CD4 T cells by cytotoxic T lymphocytes. The third is much slower and is caused by the emergence of new naive T cells from the thymus, which is indicated by the presence of Tcell receptor excision circles (TRECs) in these laterarriving cells (see Section 59).


Immunology_Janeway

Immunology_Janeway. Although HAART is effective at inhibiting HIV replication, thereby preventing the progression to AIDS and greatly decreasing transmission by those infected, it is ineffective at eradicating all viral stores. Cessation of HAART therefore leads to a rapid rebound of virus multiplication, so that patients require treatment indefinitely. This, coupled with the sideeffects and high cost of HAART, have stimulated investigation into other targets to block viral replication (Fig. 13.39) as well as ways of eliminating viral reservoirs to eradicate infection permanently. New classes of antiHIV replication drugs include viral entry inhibitors, which block the binding of gp120 to CCR5 or block viral fusion by inhibiting gp41; and viral integrase inhibitors, which block the insertion of the reversetranscribed viral genome into the host DNA. Another approach under development is to enhance the activity of HIV restriction factors, including APOBEC (see Section 1327) and TRIM 5α. APOBEC causes


Immunology_Janeway

Immunology_Janeway. viral genome into the host DNA. Another approach under development is to enhance the activity of HIV restriction factors, including APOBEC (see Section 1327) and TRIM 5α. APOBEC causes extensive mutation of newly formed HIV cDNA to destroy its coding and replicative capacity, and TRIM 5α limits HIV1 infections by targeting the viral nucleocapsid and preventing the uncoating and release of viral RNA after it enters cells.


Immunology_Janeway

Immunology_Janeway. Given the success of HAART in blocking active viral replication, the inability of existing therapies to purge reservoirs of latently infected cells has become the greatest barrier to a cure. To overcome this, strategies are being considered that would induce viral replication in latently infected cells in combination with measures to enhance immune clearance of virus and infected cells. Examples of ways to activate latent virus include the administration of cytokines that activate viral transcription and replication (for example, IL2, IL6, and TNFα), or the use of agents that target epigenetic modifiers, such as histone deacetylase (HDAC) inhibitors, that can activate latent provirus. To date, however, no clinical trial using agents that target latent viral reservoirs has shown a significant reduction in viral load over that gained from HAART alone. Indeed, it was recently discovered that the activation of viral replication in latently infected cells is intrinsically stochastic, so


Immunology_Janeway

Immunology_Janeway. reduction in viral load over that gained from HAART alone. Indeed, it was recently discovered that the activation of viral replication in latently infected cells is intrinsically stochastic, so that many immune cells harboring latent provirus will fail to activate viral replication in any given cycle of cellular activation. This adaptation of HIV to avoid elimination of latently infected cells could represent a formidable barrier to strategies aimed at ‘flushing out’ latent virus so that it can be eliminated.


Immunology_Janeway

Immunology_Janeway. Viral entry inhibitors Viral integrase inhibitors Virus assembly Protease inhibitors Reverse transcriptase inhibitors. Nucleoside analogs and non-nucleoside analogs interrupt transcription of viral RNA into viral cDNA Fig. 3.39 Possible targets for interference with the HIV life and budding of infectious virions. as yet, only drugs that inhibit cycle. in principle, HiV could be attacked by therapeutic drugs at reverse transcriptase and protease action have been developed. multiple points in its life cycle: virus entry, reverse transcription of viral Combination therapy using different kinds of drugs is more effective Rna, insertion of viral cDna into cellular Dna by the viral integrase, than using a single drug. cleavage of viral polyproteins by the viral protease, and assembly


Immunology_Janeway

Immunology_Janeway. An alternative strategy for cure has been highlighted in a single HIV patient who underwent hematopoietic stemcell transplantation (HSCT) for treatment of leukemia in Berlin (hence referred to as the Berlin patient). By using a stemcell donor who was homozygous for the CCR5Δ32 coreceptor mutation, the patient was reconstituted with immune cells resistant to viral propagation. The patient’s CD4 Tcell counts rebounded and he was found to be free of any evidence of HIV infection (or leukemia) following cessation of antiretroviral therapy posttransplant. He has remained so for more than 5 years, suggesting that he has been cured of infection. In view of the large number of infected individuals worldwide, the risk of complications with HSCT, and rarity of HLAmatched CCR5deletant donors, this will never be a practical approach for cure at the population level. Moreover, there is a risk of progression or reinfection posttransplant by CXCR4tropic viral variants. This outcome does, however,


Immunology_Janeway

Immunology_Janeway. will never be a practical approach for cure at the population level. Moreover, there is a risk of progression or reinfection posttransplant by CXCR4tropic viral variants. This outcome does, however, dramatically establish that eradication of a latency reservoir (in this case by inductive chemoirradiation therapy for leukemia) combined with blockade of viral replication—whether by genetic or therapymediated interventions— might achieve a permanent cure.


Immunology_Janeway

Immunology_Janeway. 13-36 In the course of infection HIV accumulates many mutations, which can result in the outgrowth of drug-resistant variants.


Immunology_Janeway

Immunology_Janeway. The rapid replication of HIV, with the generation of 109 to 1010 virions every day, is coupled with a mutation rate of approximately 3 × 10–5 substitutions per nucleotide per cycle of replication, and thus leads to the generation of many variants of HIV in a single infected patient in the course of a day. This high mutation rate arises from the errorprone nature of retroviral replication and poses a formidable challenge to the immune system. Reverse transcriptase lacks the proofreading mechanisms of cellular DNA polymerases, and the RNA genomes of retroviruses are copied into DNA with relatively low fidelity. Thus, although primary infection is typically established by a single founder virus, numerous variants of HIV, called quasispecies, rapidly develop within an infected individual. This phenomenon was first recognized in HIV and has since proved to be common to all lentiviruses.


Immunology_Janeway

Immunology_Janeway. As a consequence of its high variability, HIV rapidly develops resistance to antiviral drugs, much as it develops escape mutants that evade Tcell recognition (see Section 1331). When drug is administered, viral variants with mutations that confer resistance emerge and multiply until the previous levels of virus are regained. Resistance to some viral protease inhibitors requires only a single mutation and appears after only a few days (Fig. 13.40); resistance to some inhibitors of reverse transcriptase develops in a similarly short time. In contrast, resistance to the nucleoside analog zidovudine takes months to develop, as it requires three or four mutations in the viral reverse transcriptase. Because of the relatively rapid appearance of resistance to antiHIV drugs, successful drug treatment has typically depended on combination therapy, where


Immunology_Janeway

Immunology_Janeway. Fig. 13.40 Resistance of HIV to protease inhibitors develops rapidly. after the administration of a single protease inhibitor drug to a patient with HiV there is a precipitous fall in plasma levels of viral Rna, with a half-life of about 2 days (top panel). this is accompanied by an initial rise in the number of CD4 t cells in peripheral blood (center panel). Within days of starting the drug, mutant drug-resistant variants can be detected in plasma (bottom panel) and in peripheral blood lymphocytes. after only 4 weeks of treatment, viral Rna levels and CD4 lymphocyte levels have returned to their original pre-drug levels, and 100% of plasma HiV is present as the drug-resistant mutant. the chance of simultaneous resistance mutations in multiple HIV proteins is virtually nil. Nevertheless, monotherapy with newer generation antiretroviral agents has proven effective in patients with low viral loads at the onset of treatment.


Immunology_Janeway

Immunology_Janeway. 13-37 Vaccination against HIV is an attractive solution but poses many difficulties. Although the effectiveness of HAART in restraining HIV replication has profoundly altered the natural history and transmission rates of HIV infection, a safe and effective vaccine for the prevention of HIV infection and AIDS remains the ultimate goal. Ideally, an effective vaccine would elicit both broadly neutralizing antibodies that block viral entry into target cells (that is, antigp120) and effective cytolytic Tcell responses, to both prevent and control HIV infection, respectively. However, no such vaccine has yet been developed, and its attainment is fraught with difficulties that have not been faced in the development of vaccines against other diseases.


Immunology_Janeway

Immunology_Janeway. The main problem is the nature of the infection itself, featuring a virus that directly undermines the central component of adaptive immunity—the CD4 T cell—and that proliferates and mutates extremely rapidly to cause sustained infection in the face of strong cytotoxic Tcell and antibody responses. The development of vaccines that could be administered to patients already infected, to boost immune responses and prevent progression to AIDS, has been considered, as have prophylactic vaccines that would prevent initial infection. The development of therapeutic vaccination in those already infected would be extremely difficult. As discussed in the previous section, HIV evolves in individual patients by the selective proliferation of mutant viruses that escape recognition by antibodies and cytotoxic T cells. The ability of the virus to persist in latent form as a transcriptionally silent provirus invisible to the immune system might also prevent even an immunized person from clearing an


Immunology_Janeway

Immunology_Janeway. T cells. The ability of the virus to persist in latent form as a transcriptionally silent provirus invisible to the immune system might also prevent even an immunized person from clearing an infection once it has been established.


Immunology_Janeway

Immunology_Janeway. There has been more hope for prophylactic vaccination to prevent new infection. But even here, the lack of protection of the normal immune response and the sheer scale of sequence diversity among HIV strains in the infected population—there are currently thousands of different HIV strains circulating in the human population—remain significant challenges. Patients infected with one strain of virus do not seem to be resistant to closely related strains, and cases of superinfection, where two strains simultaneously infect the same cell, have also been described. This is compounded by the intrinsic difficulty in generating broadly neutralizing antibodies against HIV envelope glycoproteins (see Section 1331). Further, there remains uncertainty over what form protective immunity to HIV might take. It is now felt that induction of both effective antibody and Tcell responses will be required to achieve protective immunity, although which epitopes might provide the best targets and how best to


Immunology_Janeway

Immunology_Janeway. It is now felt that induction of both effective antibody and Tcell responses will be required to achieve protective immunity, although which epitopes might provide the best targets and how best to induce them remain undefined. Finally, the time from conception to design to performance of complete clinical trials of vaccines against HIV takes years, slowing the rate of progress; to date, few major clinical vaccine trials have been completed, and those have failed.


Immunology_Janeway

Immunology_Janeway. However, against this pessimistic background, progress has been made and there remains hope that successful vaccines might yet be developed. Various strategies are being tried in an attempt to develop vaccines against HIV, varying among delivery of recombinant HIV proteins, plasmid DNA vaccination with HIV genes (see Section 1630), delivery of HIV genes in viral vectors, or combinations thereof. Many successful vaccines against other viral diseases contain a live attenuated strain of the virus, which raises an immune response but does not cause disease (see Section 1623). There are substantial difficulties in the development of live attenuated vaccines against HIV, not least the worry of recombination between vaccine strains and wildtype viruses that would lead to a reversion to virulence. An alternative approach is the use of other viruses, such as vaccinia or adenovirus, to deliver and express HIV genes that elicit Band Tcell responses against HIV antigens. Because these viral


Immunology_Janeway

Immunology_Janeway. An alternative approach is the use of other viruses, such as vaccinia or adenovirus, to deliver and express HIV genes that elicit Band Tcell responses against HIV antigens. Because these viral vectors have already demonstrated safety in other human vaccination studies, they have been obvious choices for initial trials. Recently, there has been encouraging, albeit limited, success with this type of approach in combination with boosts using recombinant gp120. Delivery of HIV gag, pol, and env genes via a canarypox viral vector followed by boosts with HIV gp120 was shown to reduce the risk of infection in a modest but significant number of highrisk vaccine recipients. This represents the first demonstration of any degree of efficacy in a large HIV vaccine trial to date. Perhaps as important, data from this study provided insights into the type of immune response that correlated with protection, indicating that the induction of non neutralizing antibodies that elicit ADCC (for example,


Immunology_Janeway

Immunology_Janeway. data from this study provided insights into the type of immune response that correlated with protection, indicating that the induction of non neutralizing antibodies that elicit ADCC (for example, IgG3 isotype) might provide protection. Because neutralizing antibodies against HIV have proven so difficult to elicit, this provides encouragement that they might not be required. Further, a study that used a cytomegalovirus (CMV) vector to deliver SIV genes to rhesus monkeys showed that potent CTL responses were induced. Although these CTL responses did not prevent infection by a pathogenic SIV strain, they did result in clearance of virus in about half of the monkeys vaccinated after its systemic spread. This unprecedented result suggests that the viral vector used for delivery of HIV genes—in this case a vector that produces HIV antigens for prolonged periods after vaccination—might play an important role in the type and amplitude of the antiviral CD8 Tcell response elicited, and


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Immunology_Janeway. genes—in this case a vector that produces HIV antigens for prolonged periods after vaccination—might play an important role in the type and amplitude of the antiviral CD8 Tcell response elicited, and protection might be achieved by an effective Tcell response alone. Additional studies will be needed to determine whether combination vaccines that elicit the appropriate non neutralizing antibodies and robust CD8 Tcell responses might achieve protection even in the absence of neutralizing antibodies.


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Immunology_Janeway. In addition to the biological obstacles to developing effective HIV vaccines, there are difficult ethical issues. It would be unethical to conduct a vaccine trial without trying at the same time to minimize the exposure of a vaccinated population to the virus itself. The effectiveness of a vaccine can, however, only be assessed in a population in which the exposure rate to the virus is high enough to assess whether vaccination protects against infection. This means that initial vaccine trials might have to be conducted in countries where the incidence of infection is very high and public health measures have not yet succeeded in reducing the spread of HIV. 13-38 Prevention and education are important in controlling the spread of HIV and AIDS.


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Immunology_Janeway. The spread of HIV can be prevented if precautions are taken by those already infected and those who are uninfected but at risk for exposure. The advent of HAART represents a major advance in blocking the transmission of HIV from infected people due to its ability to greatly reduce viral titers in body fluids. However, most who are infected with HIV do not have access to HAART, as it is expensive and requires lifelong treatment, and many of those infected are unaware that they carry the virus. Even where HAART is unavailable, access to regular screening for those at risk is critical to inform those infected so they can take measures to avoid passing the virus to others. This, in turn, requires strict confidentiality and mutual trust. A barrier to the control of HIV is reluctance of individuals to find out whether they are infected, especially as one of the consequences of a positive HIV test is stigmatization by society. Here, education becomes an important component of the prevention


Immunology_Janeway

Immunology_Janeway. to find out whether they are infected, especially as one of the consequences of a positive HIV test is stigmatization by society. Here, education becomes an important component of the prevention strategy, both to remove the stigma and to provide guidance on how transmission of the virus can be prevented.


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Immunology_Janeway. Precautions that can be taken by uninfected individuals are relatively inexpensive and involve measures to protect against contact with body fluids, such as semen, blood, blood products, or milk, from people who are infected. It has been repeatedly demonstrated that this is sufficient to prevent infection, as exemplified by healthcare workers who care for AIDS patients for long periods without seroconversion or signs of infection. The routine use of condoms greatly reduces the risk of HIV transmission, as does restraint from breastfeeding by infected mothers of newborns. Male circumcision also reduces transmission rates, as the foreskin is a major site of viral entry in uncircumcised males. Additional measures that have been considered include the use of microbicidal gels or suppositories, improvements in which have led to products that show promise in recent trials. Some of these agents can also reduce the transmission of other sexually transmitted diseases (for example, genital


Immunology_Janeway

Immunology_Janeway. improvements in which have led to products that show promise in recent trials. Some of these agents can also reduce the transmission of other sexually transmitted diseases (for example, genital herpes) that increase the risk of HIV transmission. Finally, there is increasing interest in the prophylactic use of antiretroviral drugs (referred to as preexposure prophylaxis, or PrEP), which are administered either topically or orally to individuals at high risk for contracting HIV. To date, two reverse transcriptase inhibitors have shown efficacy in trials, and combined daily use of both drugs taken orally has demonstrated over 90% reduction in the risk of HIV infection. Moreover, use of antiretroviral therapy immediately postexposure—for example, in hospital workers exposed to contaminated blood by accidental needlestick—substantially reduces the risk of acquiring HIV. One concern with this approach is the risk of developing drug resistance in those who do contract HIV while on PrEP,


Immunology_Janeway

Immunology_Janeway. blood by accidental needlestick—substantially reduces the risk of acquiring HIV. One concern with this approach is the risk of developing drug resistance in those who do contract HIV while on PrEP, particularly in individuals with poor adherence to the dosing regimen. Although the significance of this risk has yet to be established, it remains an issue. Nevertheless, testing of new PrEP strategies based on additional antiretrovirals or of longacting formulations that reduce the risk of poor compliance represents areas of considerable promise.


Immunology_Janeway

Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Infection with the human immunodeficiency virus (HIV) is the cause of acquired immune deficiency syndrome (AIDS). Although substantial gains in curbing the rate of spread of HIV have been made, this worldwide epidemic continues to spread, especially through heterosexual contact in lessdeveloped countries. HIV is an enveloped retrovirus that replicates in cells of the immune system. Viral entry requires the presence of CD4 and a particular chemokine receptor, and the viral cycle is dependent on transcription factors found in activated T cells. Infection with HIV causes a loss of CD4 T cells and an acute viremia that rapidly subsides as cytotoxic Tcell responses develop, but HIV infection is not eliminated by this immune response. HIV establishes a state of persistent infection in which the virus is continually replicating in newly infected cells. Current treatment consists of combinations of antiviral drugs that block viral replication and cause a rapid decrease in virus levels and a


Immunology_Janeway

Immunology_Janeway. virus is continually replicating in newly infected cells. Current treatment consists of combinations of antiviral drugs that block viral replication and cause a rapid decrease in virus levels and a slow increase in CD4 Tcell counts. The main effect of HIV infection is the destruction of CD4 T cells, which occurs through the direct cytopathic effects of HIV infection and through killing by CD8 cytotoxic T cells. As CD4 Tcell counts wane, the body becomes progressively more susceptible to opportunistic infection. Eventually, most untreated HIVinfected individuals develop AIDS and die; however, a small minority, socalled longterm nonprogressors, remain healthy for many years with no apparent ill effects of infection. We hope to be able to learn from these people how infection with HIV can be controlled. The existence of these people, and of others who seem to have been naturally immunized against infection, gives hope that it will be possible to develop effective vaccines against HIV.


Immunology_Janeway

Summary to Chapter 13.

Immunology_Janeway. Summary to Chapter 13.


Immunology_Janeway

Immunology_Janeway. Whereas most infections elicit protective immunity, successful pathogens have developed some means of at least partly resisting the immune response and can cause serious, sometimes persistent, disease. Some individuals have inherited deficiencies in different components of the immune system, making them highly susceptible to certain classes of infectious agents. Persistent infections and inherited immunodeficiency diseases illustrate the importance of innate and adaptive immunity in effective host defense, and present ongoing challenges for immunological research. The human immunodeficiency virus (HIV), which leads to acquired immune deficiency syndrome (AIDS), combines the characteristics of a persistent infectious agent with the ability to create immunodeficiency in its human host, a combination that is usually slowly lethal to the patient. The key to fighting new pathogens such as HIV is to increase our understanding of the basic properties of the immune system and its role in


Immunology_Janeway

Immunology_Janeway. a combination that is usually slowly lethal to the patient. The key to fighting new pathogens such as HIV is to increase our understanding of the basic properties of the immune system and its role in combating infection.


Immunology_Janeway

Immunology_Janeway. Questions. 13.1 Matching: Match the following gene defects with the associated primary immunodeficiency. 13.2 True or False: individuals with mutations in the genes encoding the il-12 p40 subunit are susceptible not only to pathogens such as M. tuberculosis that require a tH1 response, but type 3 (tH17) responses are also affected. 13.3 Short Answer: name two genetic defects that lead to the absence of CD8+ t cells with CD4+ t cells preserved, and one genetic defect that leads to the absence of CD4+ t cells with CD8+ t cells preserved. 13.4 Short Answer: Both CD40l deficiency and aiD deficiency cause hyper-igM syndrome, but t-cell function is severely impaired in CD40l deficiency and preserved in aiD deficiency. Why? 13.5 True or False: Common variable immunodeficiency (CViD) severely impairs both t-cell and antibody responses. 13.6 Multiple Choice: Which of the following hereditary immune disorders does not have an autoimmune or autoinflammatory phenotype?


Immunology_Janeway

Immunology_Janeway. 13.6 Multiple Choice: Which of the following hereditary immune disorders does not have an autoimmune or autoinflammatory phenotype? A. autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (aPeCeD), caused by defects in B. Familial Mediterranean fever (FMF), caused by pyrin mutations C. Ommen syndrome, caused by RAG1 or RAG2 hypomorphic mutations D. Wiskott–aldrich syndrome (WaS), caused by WaS deficiency E. Hyper-ige syndrome (also called Job’s syndrome), caused by Stat3 or DOCK8 mutations


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Immunology_Janeway. D. Wiskott–aldrich syndrome (WaS), caused by WaS deficiency E. Hyper-ige syndrome (also called Job’s syndrome), caused by Stat3 or DOCK8 mutations F. Chronic granulomatous disease (CGD), caused by production of reactive oxygen species in phagocytes 13.7 Multiple Choice: Pyogenic bacteria are protected by polysaccharide capsules against recognition by receptors on macrophages and neutrophils. antibody-dependent opsonization is one of the mechanisms utilized by phagocytes to ingest and destroy these bacteria. Which of the following diseases or deficiencies directly affects a mechanism by which the immune system controls infection by these pathogens? A. il-12 p40 deficiency B. Defects in AIRE C. WaSp deficiency D. Defects in C3 13.8 Multiple Choice: Defects in which of the following genes have a phenotype similar to defects in ELA2, the gene that encodes neutrophil elastase? A. GFI1 B. CD55 (encodes DaF) C. CD59


Immunology_Janeway

Immunology_Janeway. A. GFI1 B. CD55 (encodes DaF) C. CD59 D. XIAP 13.9 Matching: Match each protein to the associated 13.10 Multiple Choice: Which of the following pathogens primarily evade(s) the immune system by antigenic variation? A. influenza a virus B. Herpes simplex virus-1 C. Cytomegalovirus D. Trypanosoma brucei E. Plasmodium falciparum F. Hepatitis B virus 13.11 Human immunodeficiency virus (HiV) produces various immunoevasins. One of these, nef, is exceptionally pleiotropic and a major target of CD8+ t-cell responses. Which of the following is not one of the functions of nef? A. inhibition of the restriction factor SaMHD1 B. MHC class i downregulation General references. Alcami, A., and Koszinowski, U.H.: Viral mechanisms of immune evasion. Immunol. Today 2000, 21:447–455. De Cock, K.M., Mbori-Ngacha, D., and Marum, E.: Shadow on the continent: public health and HIV/AIDS in Africa in the 21st century. Lancet 2002, 360:67–72.


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Immunology_Janeway. De Cock, K.M., Mbori-Ngacha, D., and Marum, E.: Shadow on the continent: public health and HIV/AIDS in Africa in the 21st century. Lancet 2002, 360:67–72. Finlay, B.B., and McFadden, G.: Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 2006, 124:767–782. Hill, A.V.: The immunogenetics of human infectious diseases. Annu. Rev. Immunol. 1998, 16:593–617. Lederberg, J.: Infectious history. Science 2000, 288:287–293. Notarangelo, L.D.: Primary immunodeficiencies. J. Allergy Clin. Immunol. 2010, 125:S182–S194. Xu, X.N., Screaton, G.R., and McMichael, A.J.: Virus infections: escape, resistance, and counterattack. Immunity 2001, 15:867–870. Section references. 13-1 A history of repeated infections suggests a diagnosis of immunodeficiency. Carneiro-Sampaio, M., and Coutinho, A.: Immunity to microbes: lessons from primary immunodeficiencies. Infect. Immun. 2007, 75:1545–1555.


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Immunology_Janeway. Carneiro-Sampaio, M., and Coutinho, A.: Immunity to microbes: lessons from primary immunodeficiencies. Infect. Immun. 2007, 75:1545–1555. Cunningham-Rundles, C., and Ponda, P.P.: Molecular defects in Tand B-cell primary immunodeficiency diseases. Nat. Rev. Immunol. 2005, 5:880–892. C. CD4 downregulation D. MHC class ii downregulation E. Sustaining t-cell activation 13.12 Fill-in-the-Blanks: Human immunodeficiency virus (HiV) is a retrovirus that is classified as such because it contains a ____________ enzyme. it infects host cells via its envelope binding to the ________ receptor and either the _______ or _______ co-receptor. When an individual becomes infected, they mount an immune response that results in the production of anti-HiV antibodies, a process called __________. CD8+ t-cell responses are also generated, but HiV can acquire ________ that allow it to evade recognition by these Ctls.


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Immunology_Janeway. 13.13 Multiple Choice: Which of the following is not a genetic variant that reduces susceptibility to HiV infection or slows protections to aiDS? A. Mutant CCR5 allele B. Mutant CXCR4 allele C. Certain Hla class i alleles D. Possessing KiR3DS1 with certain Hla-B alleles 13-2 Primary immunodeficiency diseases are caused by inherited gene defects. Bolze, A., Mahlaoui, N., Byun, M., Turner, B., Trede, N., Ellis, S.R., Abhyankar, A., Itan, Y., Patin, E., Brebner, S., et al.: Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 2013, 340:976–978. Cunningham-Rundles, C., and Ponda, P.P.: Molecular defects in Tand B-cell primary immunodeficiency diseases. Nat. Rev. Immunol. 2005, 5:880–892. Kokron, C.M., Bonilla, F.A., Oettgen, H.C., Ramesh, N., Geha, R.S., and Pandolfi, F.: Searching for genes involved in the pathogenesis of primary immunodeficiency diseases: lessons from mouse knockouts. J. Clin. Immunol. 1997, 17:109–126.


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Immunology_Janeway. Koss, M., Bolze, A., Brendolan, A., Saggese, M., Capellini, T.D., Bojilova, E., Boisson, B., Prall, O.W.J., Elliott, D.A., Solloway, M., et al.: Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev. Cell 2012, 22:913–926. Marodi, L., and Notarangelo, L.D.: Immunological and genetic bases of new primary immunodeficiencies. Nat. Rev. Immunol. 2007, 7:851–861. 13-3 Defects in T-cell development can result in severe combined immunodeficiencies. Buckley, R.H., Schiff, R.I., Schiff, S.E., Markert, M.L., Williams, L.W., Harville, T.O., Roberts, J.L., and Puck, J.M.: Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J. Pediatr. 1997, 130:378–387. Leonard, W.J.: The molecular basis of X linked severe combined immuno-13-8 Defects in B-cell development result in deficiencies in antibody deficiency. Annu. Rev. Med. 1996, 47:229–239.


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Immunology_Janeway. Leonard, W.J.: The molecular basis of X linked severe combined immuno-13-8 Defects in B-cell development result in deficiencies in antibody deficiency. Annu. Rev. Med. 1996, 47:229–239. Leonard, W.J.: Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 2001, 1:200–208. Stephan, J.L., Vlekova, V., Le Deist, F., Blanche, S., Donadieu, J., De Saint-Basile, G., Durandy, A., Griscelli, C., and Fischer, A.: Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J. Pediatr. 1993, 123:564–572. 13-4 SCID can also be due to defects in the purine salvage pathway. Hirschhorn, R.: Adenosine deaminase deficiency: molecular basis and recent developments. Clin. Immunol. Immunopathol. 1995, 76:S219–S227. 13-5 Defects in antigen receptor gene rearrangement can result in SCID. Bosma, M.J., and Carroll, A.M.: The SCID mouse mutant: definition, characterization, and potential uses. Annu. Rev. Immunol. 1991, 9:323–350.


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Immunology_Janeway. Bosma, M.J., and Carroll, A.M.: The SCID mouse mutant: definition, characterization, and potential uses. Annu. Rev. Immunol. 1991, 9:323–350. Fugmann, S.D.: DNA repair: breaking the seal. Nature 2002, 416:691–694. Gennery, A.R., Cant, A.J., and Jeggo, P.A.: Immunodeficiency associated with DNA repair defects. Clin. Exp. Immunol. 2000, 121:1–7. Moshous, D., Callebaut, I., de Chasseval, R., Corneo, B., Cavazzana-Calvo, M., Le Deist, F., Tezcan, I., Sanal, O., Bertrand, Y., Philippe, N., et al.: Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 2001, 105:177–186. 13-6 Defects in signaling from T-cell antigen receptors can cause severe immunodeficiency. Castigli, E., Pahwa, R., Good, R.A., Geha, R.S., and Chatila, T.A.: Molecular basis of a multiple lymphokine deficiency in a patient with severe combined immunodeficiency. Proc. Natl Acad. Sci. USA 1993, 90:4728–4732.


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Immunology_Janeway. Kung, C., Pingel, J.T., Heikinheimo, M., Klemola, T., Varkila, K., Yoo, L.I., Vuopala, K., Poyhonen, M., Uhari, M., Rogers, M., et al.: Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat. Med. 2000, 6:343–345. Roifman, C.M., Zhang, J., Chitayat, D., and Sharfe, N.: A partial deficiency of interleukin-7R α is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood 2000, 96:2803–2807. 13-7 Genetic defects in thymic function that block T-cell development result in severe immunodeficiencies. Coffer, P.J., and Burgering, B.M.: Forkhead-box transcription factors and their role in the immune system. Nat. Rev. Immunol. 2004, 4:889–899. DiSanto, J.P., Keever, C.A., Small,T.N., Nicols, G.L., O’Reilly, R.J., and Flomenberg, N.: Absence of interleukin 2 production in a severe combined immunodeficiency disease syndrome with T cells. J. Exp. Med. 1990, 171:1697–1704.


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Immunology_Janeway. DiSanto, J.P., Rieux Laucat, F., Dautry Varsat, A., Fischer, A., and de Saint Basile, G.: Defective human interleukin 2 receptor γ chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. Proc. Natl Acad. Sci. USA 1994, 91:9466–9470. Gadola, S.D., Moins-Teisserenc, H.T., Trowsdale, J., Gross, W.L., and Cerundolo, V.: TAP deficiency syndrome. Clin. Exp. Immunol. 2000, 121:173–178. Gilmour, K.C., Fujii, H., Cranston, T., Davies, E.G., Kinnon, C., and Gaspar, H.B.: Defective expression of the interleukin-2/interleukin-15 receptor β subunit leads to a natural killer cell-deficient form of severe combined immunodeficiency. Blood 2001, 98:877–879. Grusby, M.J., and Glimcher, L.H.: Immune responses in MHC class II-deficient mice. Annu. Rev. Immunol. 1995, 13:417–435.


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Immunology_Janeway. Grusby, M.J., and Glimcher, L.H.: Immune responses in MHC class II-deficient mice. Annu. Rev. Immunol. 1995, 13:417–435. Pignata, C., Gaetaniello, L., Masci, A.M., Frank, J., Christiano, A., Matrecano, E., and Racioppi, L.: Human equivalent of the mouse Nude/SCID phenotype: longterm evaluation of immunologic reconstitution after bone marrow transplantation. Blood 2001, 97:880–885. Steimle, V., Reith, W., and Mach, B.: Major histocompatibility complex class II deficiency: a disease of gene regulation. Adv. Immunol. 1996, 61:327–340. production that cause an inability to clear extracellular bacteria and some viruses. Bruton, O.C.: Agammaglobulinemia. Pediatrics 1952, 9:722–728. Conley, M.E.: Genetics of hypogammaglobulinemia: what do we really know? Curr. Opin. Immunol. 2009, 21:466–471. Lee, M.L., Gale, R.P., and Yap, P.L.: Use of intravenous immunoglobulin to prevent or treat infections in persons with immune deficiency. Annu. Rev. Med. 1997, 48:93–102.


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Immunology_Janeway. Lee, M.L., Gale, R.P., and Yap, P.L.: Use of intravenous immunoglobulin to prevent or treat infections in persons with immune deficiency. Annu. Rev. Med. 1997, 48:93–102. Notarangelo, L.D.: Immunodeficiencies caused by genetic defects in protein kinases. Curr. Opin. Immunol. 1996, 8:448–453. Preud’homme, J.L., and Hanson, L.A.: IgG subclass deficiency. Immunodefic. Rev. 1990, 2:129–149. 13-9 Immune deficiencies can be caused by defects in B-cell or T-cell activation and function that lead to abnormal antibody responses. Burrows, P.D., and Cooper, M.D.: IgA deficiency. Adv. Immunol. 1997, 65:245–276. Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., et al.: X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nat. Genet. 2001, 27:277–285.


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Immunology_Janeway. Durandy, A., and Honjo, T.: Human genetic defects in class-switch recombination (hyper-IgM syndromes). Curr. Opin. Immunol. 2001, 13:543–548. Ferrari, S., Giliani, S., Insalaco, A., Al Ghonaium, A., Soresina, A.R., Loubser, M., Avanzini, M.A., Marconi, M., Badolato, R., Ugazio, A.G., et al.: Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc. Natl Acad. Sci. USA 2001, 98:12614–12619. Harris, R.S., Sheehy, A.M., Craig, H.M., Malim, M.H., and Neuberger, M.S.: DNA deamination: not just a trigger for antibody diversification but also a mechanism for defense against retroviruses. Nat. Immunol. 2003, 4:641–643. Minegishi, Y.: Hyper-IgE syndrome. Curr. Opin. Immunol. 2009, 21:487–492. Park, M.A., Li, J.T., Hagan, J.B., Maddox, D.E., and Abraham, R.S.: Common variable immunodeficiency: a new look at an old disease. Lancet 2008, 372:489–503.


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Immunology_Janeway. Park, M.A., Li, J.T., Hagan, J.B., Maddox, D.E., and Abraham, R.S.: Common variable immunodeficiency: a new look at an old disease. Lancet 2008, 372:489–503. Thrasher, A.J., and Burns, S.O.: WASP: a key immunological multitasker. Nat. Rev. Immunol. 2010, 10:182–192. Yel, L.: Selective IgA deficiency. J. Clin. Immunol. 2010, 30:10–16. Yong, P.F., Salzer, U., and Grimbacher, B.: The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunol. Rev. 2009, 229:101–113. are pinpointed by genetic deficiencies of cytokine pathways central to type 1/TH1 and type 3/TH17 responses. Browne, S.K.: Anticytokine autoantibody-associated immunodeficiency. Annu. Rev. Immunol. 2014, 32:635–657. Casanova, J.L., and Abel, L.: Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 2002, 20:581–620.


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Immunology_Janeway. Casanova, J.L., and Abel, L.: Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 2002, 20:581–620. Dupuis, S., Dargemont, C., Fieschi, C., Thomassin, N., Rosenzweig, S., Harris, J., Holland, S.M., Schreiber, R.D., and Casanova, J.L.: Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 2001, 293:300–303. Lammas, D.A., Casanova, J.L., and Kumararatne, D.S.: Clinical consequences of defects in the IL-12-dependent interferon-γ (IFN-γ) pathway. Clin. Exp. Immunol. 2000, 121:417–425. Lanternier, F., Cypowyj, S., Picard, C., Bustamante, J., Lortholary, O., Casanova, J.-L., and Puel, A.: Primary immunodeficiencies underlying fungal infections. Curr. Opin. Pediatr. 2013, 25:736–747.


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Immunology_Janeway. Lanternier, F., Pathan, S., Vincent, Q.B., Liu, L., Cypowyj, S., Prando, C., Migaud, M., Taibi, L., Ammar-Khodja, A., Boudghene Stambouli, O., et al.: Deep dermatophytosis and inherited CARD9 deficiency. N. Engl. J. Med. 2013, 369:1704–1714. Newport, M.J., Huxley, C.M., Huston, S., Hawrylowicz, C.M., Oostra, B.A., Williamson, R., and Levin, M.: A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 1996, 335:1941–1949. Puel, A., Döffinger, R., Natividad, A., Chrabieh, M., Barcenas-Morales, G., Picard, C., Cobat,A., Ouachée-Chardin, M.,Toulon,A., Bustamante, J., et al.: Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 2010, 207:291–297.


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Immunology_Janeway. Van de Vosse, E., Hoeve, M.A., and Ottenhoff, T.H.: Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. Lancet Infect. Dis. 2004, 4:739–749. 13-11 Inherited defects in the cytolytic pathway of lymphocytes can cause uncontrolled lymphoproliferation and inflammatory responses to viral infections. de Saint Basile, G., Ménasché, G., and Fischer, A.: Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat. Rev. Immunol. 2010, 10:568–579. de Saint Basille, G., and Fischer, A.: The role of cytotoxicity in lymphocyte homeostasis. Curr. Opin. Immunol. 2001, 13:549–554. 13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the development of lymphomas.


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Immunology_Janeway. 13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the development of lymphomas. Latour, S., Gish, G., Helgason, C.D., Humphries, R.K., Pawson, T., and Veillette, A.: Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat. Immunol. 2001, 2:681–690. Morra, M., Howie, D., Grande, M.S., Sayos, J., Wang, N., Wu, C., Engel, P., and Terhorst, C.: X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu. Rev. Immunol. 2001, 19:657–682. Rigaud, S., Fondaneche, M.C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., et al.: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006, 444:110–114. 13-13 Immunodeficiency is caused by inherited defects in the development of dendritic cells.


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Immunology_Janeway. 13-13 Immunodeficiency is caused by inherited defects in the development of dendritic cells. Collin, M., Bigley, V., Haniffa, M., and Hambleton, S.: Human dendritic cell deficiency: the missing ID? Nat. Rev. Immunol. 2011, 11:575–583. Hambleton, S., Salem, S., Bustamante, J., Bigley, V., Boisson-Dupuis, S., Azevedo, J., Fortin, A., Haniffa, M., Ceron-Gutierrez, L., Bacon, C.M., et al.: IRF8 mutations and human dendritic-cell immunodeficiency. N. Engl. J. Med. 2011, 365:127–138. damage. Colten, H.R., and Rosen, F.S.: Complement deficiencies. Annu. Rev. Immunol. 1992, 10:809–834. Dahl, M., Tybjaerg-Hansen, A., Schnohr, P., and Nordestgaard, B.G.: A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J. Exp. Med. 2004, 199:1391–1399. Walport, M.J.: Complement. First of two parts. N. Engl. J. Med. 2001, 344:1058–1066. Walport, M.J.: Complement. Second of two parts. N. Engl. J. Med. 2001, 344:1140–1144.


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Immunology_Janeway. Barouch, D.H.: The quest for an HIV-1 vaccine--moving forward. N. Engl. J. Med. 2013, 369:2073–2076. Barouch, D.H., Kunstman, J., Kuroda, M.J., Schmitz, J.E., Santra, S., Peyerl, F.W., Krivulka, G.R., Beaudry, K., Lifton, M.A., Gorgone, D.A., et al.: Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002, 415:335–339. Isitman, G., Stratov, I., and Kent, S.J.: Antibody-dependent cellular cytotoxicity and Nk cell-driven immune escape in HIV Infection: Implications for HIV vaccine development. Adv. Virol. 2012, 212:637208. Letvin, N.L.: Progress and obstacles in the development of an AIDS vaccine. Nat. Rev. Immunol. 2006, 6:930–939. McMichael, A.J., and Koff, W.C.: Vaccines that stimulate T cell immunity to HIV-1: the next step. Nat. Immunol. 2014, 15:319–322. 13-38 Prevention and education are important in controlling the spread of HIV and AIDS.


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Immunology_Janeway. 13-38 Prevention and education are important in controlling the spread of HIV and AIDS. Coates, T.J., Aggleton, P., Gutzwiller, F., Des-Jarlais, D., Kihara, M., Kippax, S., Schechter, M., and van-den-Hoek, J.A.: HIV prevention in developed countries. Lancet 1996, 348:1143–1148. Decosas, J., Kane, F., Anarfi, J.K., Sodji, K.D., and Wagner, H.U.: Migration and AIDS. Lancet 1995, 346:826–828. Dowsett, G.W.: Sustaining safe sex: sexual practices, HIV and social context. AIDS 1993, 7 Suppl. 1:S257–S262. Kirby, M.: Human rights and the HIV paradox. Lancet 1996, 348:1217–1218. Nelson, K.E., Celentano, D.D., Eiumtrakol, S., Hoover, D.R., Beyrer, C., Suprasert, S., Kuntolbutra, S., and Khamboonruang, C.: Changes in sexual behavior and a decline in HIV infection among young men in Thailand. N. Engl. J. Med. 1996, 335:297–303. Weniger, B.G., and Brown, T.: The march of AIDS through Asia. N. Engl. J. Med. 1996, 335:343–345.


Immunology_Janeway

Immunology_Janeway. Weniger, B.G., and Brown, T.: The march of AIDS through Asia. N. Engl. J. Med. 1996, 335:343–345. The adaptive immune response is a critical component of host defense against infection and is essential for normal health. Antigens not associated with infectious agents sometimes elicit adaptive immune responses, and this can cause disease. One circumstance in which this happens is when harmful immunologically mediated hypersensitivity reactions known generally as allergic reactions occur in response to inherently harmless ‘environmental’ antigens such as pollen, food, and drugs.


Immunology_Janeway

Immunology_Janeway. Historically, hypersensitivity reactions due to immunological responses were classified by Gell and Coombs into four broad types, of which type I hypersensitivity reactions represented immediate-type allergic reactions mediated by IgE antibodies, with mast-cell activation the major final effector mechanism. Type II and III hypersensitivity responses were defined as those that were driven by antigen-specific IgG antibodies, the final effector mechanism being complement (type II) or FcR-bearing cellular effectors (type III). Finally, type IV hypersensitivity responses were depicted as being driven by cellular effectors, including lymphocytes and a variety of myeloid cell types. While the Gell and Coombs classification system provides an effective framework for understanding the mechanisms underlying some prototypic immunologic reactions, it is now becoming clear that most normal and pathologic host immune responses involve both the humoral and cellular arms of the immune system, and


Immunology_Janeway

Immunology_Janeway. underlying some prototypic immunologic reactions, it is now becoming clear that most normal and pathologic host immune responses involve both the humoral and cellular arms of the immune system, and that the definitions provided in Chapter 11 for types 1, 2, and 3 immune response modules provide a more thorough mechanistic context for understanding disease pathogenesis, including allergic responses (see Fig. 11.5). In most allergic reactions, such as those to food, pollen, or house dust, reactions occur because the individual has become sensitized to an innocuous anti-gen—the allergen—by producing IgE antibodies against it. This is usually a result of the formation of an unwanted type 2 immune response to the allergen. Subsequent exposure to the allergen triggers the activation of IgE-binding cells, chiefly mast cells and basophils, in the exposed tissue, leading to a series of responses that are characteristic of this type of allergic reaction. In hay fever (allergic


Immunology_Janeway

Immunology_Janeway. of IgE-binding cells, chiefly mast cells and basophils, in the exposed tissue, leading to a series of responses that are characteristic of this type of allergic reaction. In hay fever (allergic rhinoconjunctivitis), for example, symptoms occur when allergenic proteins leached out of grass or weed pollen grains come into contact with the mucous membrane of the nose and eyes. In contrast, other hypersensitivity disorders, such as allergic contact dermatitis, serum sickness, or celiac disease, are not dependent on IgE antibodies and represent unwanted immune responses driven by IgG antibodies and/or cellular immune responses.