Immunology_Janeway

Immunology_Janeway. In the previous section, we learned how specific defects in immune pathways lead to infection, often by microbes that would normally be defeated by a healthy immune system. These ‘opportunistic’ infections often dominate the clinical expression of inherited immunodeficiencies because the causative organisms are ubiquitous and abundant in the environment. A minority of microbes are true pathogens that can infect those with normal immune defenses. A defining feature of pathogens is their ability to avoid immune destruction by components of the innate and adaptive immune systems, at least long enough to replicate in the infected host and spread to new hosts. At one end of the spectrum are pathogens that establish an acute infection, replicate quickly, and find a new host before they are cleared by a successful immune response; at the other are pathogens that establish chronic infections, persisting long term in the host while evading elimination by immune defenses. Successful pathogens


Immunology_Janeway

Immunology_Janeway. by a successful immune response; at the other are pathogens that establish chronic infections, persisting long term in the host while evading elimination by immune defenses. Successful pathogens use different strategies to achieve these ends, and over millions of years of coevolution with their hosts have evolved a remarkable diversity of strategies for avoiding detection and destruction by the immune system, often employing several strategies that subvert immunity at multiple points. The antiimmune strategies employed by pathogens are as sophisticated as the immune system itself. They must be for any pathogens to achieve success against the diverse strategies that vertebrates have evolved to ensure host protection.


Immunology_Janeway

Immunology_Janeway. Viruses, bacteria, and protozoan (unicellular) or metazoan (multicellular) parasites can all act as pathogens. While fungi and helminthic (metazoan) parasites are major causes of common skin infections and intestinal worm infestation, respectively, they do not typically cause lifethreatening infections in normal people and will not be considered further here. In contrast, a select number of viruses, bacteria, and protozoan parasites are the major causes of morbidity and mortality caused by infectious agents. AIDS, tuberculosis, and malaria, caused by the human immunodeficiency virus (HIV), Mycobacterium tuberculosis, and Plasmodium falciparum, respectively, are the three largest infectious disease threats to humans; each of these pathogens infects over 100 million people worldwide and kills 1 to 2 million people annually. Although the strategies for survival within—and propagation between—hosts differ for each type of pathogen, many of the innate and adaptive immune mechanisms


Immunology_Janeway

Immunology_Janeway. and kills 1 to 2 million people annually. Although the strategies for survival within—and propagation between—hosts differ for each type of pathogen, many of the innate and adaptive immune mechanisms employed to thwart the pathogen are the same. Here we briefly consider the lifestyles of, and the principal immune responses elicited by, different types of pathogens, and the strategies the pathogens employ to evade or subvert the immune system.


Immunology_Janeway

Immunology_Janeway. strategies to avoid detection by pattern recognition receptors and destruction by antibody, complement, and antimicrobial peptides.


Immunology_Janeway

Immunology_Janeway. Extracellular bacterial pathogens replicate outside of host cells, whether on the surfaces of barrier tissues they colonize (for example, gastrointestinal or respiratory tract), or in tissue spaces or blood following invasion across barrier epithelia. Both Gramnegative and positive species are pathogenic, and, as discussed in Section 1110, they typically elicit type 3 immunity, which orchestrates neutrophilic responses, the development of opsonizing and complementfixing antibodies, and the production of antimicrobial peptides by barrier epithelial cells and immune cells that clear these microbes from barrier epithelia and prevent their invasion. Some of the MAMPS expressed by Gramnegative and positive bacteria are distinct, but share similar immunecell activating properties. Gramnegative pathogens contain LPS, a potent activator of TLR4, in their outer cell membrane, whereas the cell wall of Grampositive pathogens contains peptidoglycans, which activate TLR2 and NOD1 and NOD2. One


Immunology_Janeway

Immunology_Janeway. pathogens contain LPS, a potent activator of TLR4, in their outer cell membrane, whereas the cell wall of Grampositive pathogens contains peptidoglycans, which activate TLR2 and NOD1 and NOD2. One strategy of immune evasion used by these pathogens is therefore shielding of surface MAMPs to avoid their detection by pattern recognition receptors on immune cells (Fig. 13.17). Several Gramnegative pathogens modify the lipid A core of LPS with carbohydrates and other moieties that interfere with TLR4 binding. Indeed, some bacteria produce variants of lipid A that act as TLR4 antagonists rather than agonists. Select Grampositive pathogens have evolved mechanisms to modulate peptidoglycan recognition by NODs, or to produce hydrolases that degrade peptidoglycan.


Immunology_Janeway

Immunology_Janeway. Fig. 13.17 Mechanisms used by bacteria to subvert the host immune system. listed are examples of immune evasion/subversion mechanisms used by different strains of extracellular and intracellular bacterial pathogens. examples of the strains of bacteria that employ each mechanism are listed in the far right column (e.g., Streptococcus pneumoniae, Porphyromonus gingivalis, Pseudomonas aeruginosa, Brucella abortus, Yersinia pestis). Fig. 13.18 Host defense against Streptococcus pneumoniae is type specific. the different strains of S. pneumoniae have antigenically distinct capsular polysaccharides. the capsule prevents effective phagocytosis until the bacterium is opsonized by specific antibody and complement, allowing phagocytes to destroy it. antibody against one type of


Immunology_Janeway

Immunology_Janeway. S. pneumoniae does not cross-react with the other types, so an individual immune to one type has no protective immunity to a subsequent infection with a different type. an individual must generate a new adaptive immune response each time he or she is infected with a different type of S. pneumoniae.


Immunology_Janeway

Immunology_Janeway. A limited number of Grampositive pathogens can also shield their outer cell membrane with a thick carbohydrate capsule. In addition to inhibiting recognition of peptidoglycan and activation of the alternative pathway of complement, the capsule prevents antibody and complement deposition on the bacterial surface, thereby avoiding direct damage by the membraneattack complex of the complement cascade. The capsule also impairs clearance of the pathogen by phagocytes (see Fig. 13.17). In the case of Streptococcus pneumoniae, an important cause of bacterial pneumonia, the carbohydrate capsule also serves as a platform for antigenic variation to modulate the expression of surface antigenic epitopes recognized by antibody. Over 90 known types of S. pneumoniae are distinguished by differences in the structure of their polysaccharide capsules. The different types are distinguished by using specific antibodies as reagents in serological tests and so are often known as serotypes. Infection with


Immunology_Janeway

Immunology_Janeway. the structure of their polysaccharide capsules. The different types are distinguished by using specific antibodies as reagents in serological tests and so are often known as serotypes. Infection with one serotype can lead to typespecific immunity, which protects against reinfection with that type but not with a different serotype. Thus, from the point of view of the adaptive immune system, each serotype of S. pneumoniae represents a distinct organism, with the result that essentially the same pathogen can cause disease many times in the same individual (Fig. 13.18). Similarly, antigenic variation mediated by DNA rearrangement also occurs in bacteria and helps to account for the success of enteropathogenic E. coli, or of Neisseria species, which cause gonorrhea and meningitis. Fimbriae or pili are expressed on the bacterial surface and used for attachment to hostcell surfaces and are major antigenic targets for antibodymediated blockade of bacterial attachment and colonization. The


Immunology_Janeway

Immunology_Janeway. or pili are expressed on the bacterial surface and used for attachment to hostcell surfaces and are major antigenic targets for antibodymediated blockade of bacterial attachment and colonization. The gene locus encoding the expressed Neisseria pilus (pilE) can undergo recombination with partial pilin genes stored in ‘silent’ (pilS) loci to generate a constantly shifting pilus for display on the bacterial surface. By constantly changing the expressed pilus, the bacterium evades antibodymediated immune clearance.


Immunology_Janeway

Immunology_Janeway. Among other antiimmune strategies used by extracellular pathogens are mechanisms to inactivate the C3 convertase of the complement cascade; the expression of Fcbinding proteins that block functional antibody binding to the bacterium (for example, Protein A); and the decoration of the bacterial surface with host inhibitors of complement (for example, factor H). These bacteria have also evolved mechanisms to defeat antimicrobial peptides (AMPs; for example, defensins and cathelicidins). These small cationic and amphipathic peptides have significant antimicrobial activity by inserting into negatively charged cell membranes to generate pores that lyse the bacterium. Pathogens can alter their membrane composition to minimize AMP binding, and can produce proteases that degrade the AMPs.


Immunology_Janeway

Immunology_Janeway. An unusual feature of Gramnegative pathogens, including both extracellular and intracellular bacteria, is their capacity to inject immune modulatory bacterial proteins directly into host cells via specialized structures: the type III and type IV secretion systems (T3SS and T4SS, respectively) (Fig. 13.19). These needlelike structures, or injectisomes, assemble on the bacterial surface and provide a conduit through which bacterial proteins are secreted directly into the cytosol of target cells. A range of bacterial virulence factors that aid in subverting the host immune response are delivered via this mechanism, including bacterial factors that block signaling cascades central to the inflammatory response: NFκB and MAP kinases. Among the most remarkable of these are the Yersinia outer proteins (Yops) produced by Yersinia pestis, the causative agent of bubonic plague. Secretion of several of these factors (for example, YopH, YopE, YopO, and YopT) into phagocytes disrupts the actin


Immunology_Janeway

Immunology_Janeway. proteins (Yops) produced by Yersinia pestis, the causative agent of bubonic plague. Secretion of several of these factors (for example, YopH, YopE, YopO, and YopT) into phagocytes disrupts the actin cytoskeleton, which is essential for phagocytosis. The essential roles played by T3SS or T4SS in immune subversion by a number of Gramnegative pathogens are demonstrated by the loss of pathogenicity of mutant bacteria lacking components of these structures.


Immunology_Janeway

Immunology_Janeway. 13-20 Intracellular bacterial pathogens can evade the immune system by seeking shelter within phagocytes.


Immunology_Janeway

Immunology_Janeway. To avoid the major effectors directed against extracellular bacteria—complement and antibodies—some bacterial pathogens have evolved specialized mechanisms for surviving within macrophages, using these phagocytes as their primary host cell, as well as a vehicle for dissemination within the host. This ‘Trojan horse’ strategy is achieved by three general strategies: blockade of phagosome–lysosome fusion; escape from the phagosome into the cytosol; and resistance to killing mechanisms within the phagolysosome. Mycobacterium tuberculosis, for example, is taken up by macrophages but prevents the fusion of the phagosome with the lysosome, protecting itself from the bactericidal actions of the lysosomal contents. Other microorganisms, such as the bacterium Listeria monocytogenes, escape from the phagosome into the cytoplasm of the macrophage, where they multiply. They then spread to adjacent cells in the tissue without emerging into the extracellular environment. They do this by hijacking


Immunology_Janeway

Immunology_Janeway. phagosome into the cytoplasm of the macrophage, where they multiply. They then spread to adjacent cells in the tissue without emerging into the extracellular environment. They do this by hijacking the cytoskeletal protein actin, which assembles into filaments at the rear of the bacterium. The actin filaments drive the bacteria forward into vacuolar projections to adjacent cells; the vacuoles are then lysed by the listeria, releasing the bacteria into the cytoplasm of the adjacent cell. Moreover, Listeria has been shown to induce the formation of bacteriacontaining blebs on the surface of infected cells. These blebs which express phosphatidyl serine on the outer membrane leaflet. This membrane phospholipid is normally restricted to the inner membrane leaflet, and when exposed on the outer membrane leaflet is normally recognized by phagocytes as a signal for the uptake of apoptotic cell debris. In this way, Listeria is delivered directly to phagocytic cells, thereby avoiding attack by


Immunology_Janeway

Immunology_Janeway. membrane leaflet is normally recognized by phagocytes as a signal for the uptake of apoptotic cell debris. In this way, Listeria is delivered directly to phagocytic cells, thereby avoiding attack by antibodies.


Immunology_Janeway

Immunology_Janeway. Following uptake, Salmonella species use a type III secretion system (see Fig. 13.19) to secrete effectors such as SifA into the host cytosol and membranes in order to alter the composition of the Salmonellacontaining vacuole so as to avoid destruction. Remarkably, Salmonella can also inject factors that delay the apoptotic death of host macrophages, prolonging the phagocytes’ lifespans until their bacterial cargo can be delivered to new cellular hosts. Other actions of intracellular bacteria counter reactive oxygen species or microbicidal peptides delivered into the phagolysosome by the ingesting phagocyte. Fig. 13.19 Pathogenic bacteria use specialized secretion systems to inject effector molecules into host cells.


Immunology_Janeway

Immunology_Janeway. Fig. 13.19 Pathogenic bacteria use specialized secretion systems to inject effector molecules into host cells. a number of pathogenic Gram-negative bacteria use a complex, needle-like protein assembly—a type iii or iV secretion system, or injectisome—to inject virulence proteins into target cells to compromise host defenses and establish infection. these ‘nanoinjectors’ are assembled from more than 20 proteins, and are composed of a base that spans the two bacterial membranes, a needle that is anchored in the base and is formed by the polymerization of repeating α-helical subunits, and a tip complex that serves as a docking structure for the translocon, which penetrates the host-cell membrane to allow bacterial effector proteins to pass into the host cell.


Immunology_Janeway

Immunology_Janeway. Fig. 13.20 T-cell and macrophage responses to Mycobacterium leprae are sharply different in the two polar forms of leprosy. infection with M. leprae, whose cells stain as small dark red dots in the photographs, can lead to two very different forms of disease (top panels). in tuberculoid leprosy (left), growth of the organism is well controlled by tH1-like cells that activate infected macrophages. the tuberculoid lesion contains granulomas and is inflamed, but the inflammation is local and causes only local effects, such as peripheral nerve damage. in lepromatous leprosy (right), infection is widely disseminated and the bacilli grow uncontrolled in macrophages; in the late stages of disease there is major damage to connective tissues and to the peripheral nervous system. there are several intermediate stages between these two polar forms (not shown). the lower panel shows northern blots demonstrating that the cytokine patterns in the two polar forms of the disease are sharply


Immunology_Janeway

Immunology_Janeway. several intermediate stages between these two polar forms (not shown). the lower panel shows northern blots demonstrating that the cytokine patterns in the two polar forms of the disease are sharply different, as shown by the analysis of Rna isolated from lesions of four patients with lepromatous leprosy and four patients with tuberculoid leprosy. Cytokines typically produced by tH2 cells (il-4, il-5, and il-10) dominate in the lepromatous form, whereas cytokines produced by tH1 cells (il-2, iFn-γ, and tnF-β) dominate in the tuberculoid form. it therefore seems that tH1-like cells predominate in tuberculoid leprosy, and tH2-like cells in lepromatous leprosy. iFn-γ would be expected to activate macrophages, enhancing the killing of M. leprae, whereas il-4 can actually inhibit the induction of bactericidal activity in macrophages. Photographs courtesy of G. Kaplan; cytokine patterns courtesy of R.l. Modlin.


Immunology_Janeway

Immunology_Janeway. As a tradeoff for their intracellular lifestyle, intracellular bacteria risk activation of immune effectors that target these pathogens: NK cells and T cells. As discussed in Section 115, a major function of the type 1 immune response is activation of NK cells and TH1 cells that activate phagocytes for enhanced intracellular killing by secretion of IFNγ or expression of CD40L. Additionally, those intracellular pathogens that have evolved mechanisms for escape of the phagosome, such as Listeria, generate cytosolic peptides that feed the MHC class I antigen presentation pathway and thus induce cytotoxic Tcell responses that target their host cell for destruction. In leprosy, a disease caused by skin and peripheral nerve infection with Mycobacterium leprae, effective host defense requires macrophage activation by NK and TH1 cells (Fig. 13.20).


Immunology_Janeway

Immunology_Janeway. Cytokine patterns in leprosy lesions TNF-˜IFN-°IL-2 IL-4 IL-5 IL-10 Lepromatous TH2 cytokinesTH1 cytokines Lepromatous Tuberculoid Tuberculoid Lepromatous leprosy Organisms show ˜orid growth in macrophages High infectivity Hypergammaglobulinemia Disseminated infection. Bone, cartilage, and diffuse nerve damage Low or absent T-cell responsiveness. No response to M. leprae antigens Infection with Mycobacterium leprae can result in different clinical forms of leprosy There are two polar forms, tuberculoid and lepromatous leprosy, but several intermediate forms also exist Normal T-cell responsiveness. Speciÿc response to M. leprae antigens Tuberculoid leprosy Organisms present at low to undetectable levels Low infectivity Normal serum immunoglobulin levels Granulomas and local in˜ammation. Peripheral nerve damage


Immunology_Janeway

Immunology_Janeway. Like M. tuberculosis, M. leprae is able to persist and grow in macrophage vesicles and is normally restrained, but not cleared, by a type 1 host response. In patients who mount normal type 1 immune responses, few live bacteria are found, little antibody is produced, and, although skin and peripheral nerves are damaged by the inflammatory responses associated with macrophage activation, the disease progresses slowly and the patients typically survive. Because of its similarities to tuberculosis, this variant is called tuberculoid leprosy. This is in contrast to lepromatous leprosy, in which type 1 responses to M. leprae are deficient and an ineffective type 2 response is mounted instead. This results in abundant growth of the bacterium in macrophages and gross tissue destruction that is eventually fatal, if untreated. Although high levels of antibacterial antibodies are produced in patients with lepromatous leprosy, probably due to the high bacterial load, the antibodies are


Immunology_Janeway

Immunology_Janeway. that is eventually fatal, if untreated. Although high levels of antibacterial antibodies are produced in patients with lepromatous leprosy, probably due to the high bacterial load, the antibodies are ineffective at controlling infection because they do not reach the intracellular bacteria.


Immunology_Janeway

Immunology_Janeway. 13-21 Immune evasion is also practiced by protozoan parasites. Most common protozoan parasites, such as Plasmodium and Trypanosoma species, have complex life cycles, part of which occurs in humans and part of which occurs in an intermediate host, such as an arthropod vector (for example, mosquitoes, flies, or ticks). The route of transmission of these organisms by their intermediate host is unusual, in that the normal barriers to infection are bypassed when the infectious agent is directly delivered to blood by a bite or the taking of a blood meal. Thus, many of the normal innate immune defenses associated with barrier function are completely bypassed during infection. Further, the most successful of these organisms have developed complex and varied immune evasion strategies that often result in ‘hideandseek’ chronic infections characterized by episodic disease manifestations, despite their eliciting antibody and cellmediated adaptive immune responses.


Immunology_Janeway

Immunology_Janeway. As described above for some bacterial pathogens (see Section 1319), Trypanosoma brucei, a causative agent of trypanosomiasis, or sleeping sickness, has evolved a remarkable capacity for antigenic variation to evade the antibody response elicited in infected humans. The trypanosome is coated with a single type of glycoprotein, the variantspecific glycoprotein (VSG), which elicits a potent protective antibody response that rapidly clears most of the parasites. The trypanosome genome, however, contains about 1000 VSG genes, each encoding a protein with distinct antigenic properties. A VSG gene is expressed by being placed into the active expression site in the parasite genome. Only one VSG gene is expressed at a time, and it can be changed by a gene rearrangement that places a new VSG gene into the expression site (Fig. 13.21). So, under the selective pressure of an effective host antibody response, the few trypanosomes within the population that express a different VSG escape


Immunology_Janeway

Immunology_Janeway. VSG gene into the expression site (Fig. 13.21). So, under the selective pressure of an effective host antibody response, the few trypanosomes within the population that express a different VSG escape elimination and multiply to cause a recurrence of disease (see Fig. 13.21, bottom panel). Antibodies are then made against the new VSG, and the whole cycle is repeated, resulting in periods of active and quiescent disease. The chronic cycles of antigen clearance lead to immunecomplex damage and


Immunology_Janeway

Immunology_Janeway. Fig. 13.21 Antigenic variation in trypanosomes allows them to escape immune surveillance. the surface of a trypanosome is covered with a variant-specific glycoprotein (VSG). each trypanosome has about 1000 genes encoding different VSGs, but only the gene in a specific expression site within the telomere at one end of the chromosome is active. although several genetic mechanisms have been observed for changing the VSG gene expressed, the usual mechanism is gene conversion. an inactive gene, which is not at the telomere, is copied and transposed into the telomeric expression site, where it becomes active. When an individual is first infected, antibodies are raised against the VSG initially expressed by the trypanosome population. a small number of trypanosomes spontaneously switch their VSG gene to a new type, and although the host antibody eliminates the initial variant, the new variant is unaffected. as the new variant grows, the whole sequence of events is repeated.


Immunology_Janeway

Immunology_Janeway. inflammation, and eventually to neurological damage, resulting finally in the coma that gives sleeping sickness its name. The cycles of evasive action make trypanosome infections very difficult for the immune system to defeat, and they are a major health problem in Africa.


Immunology_Janeway

Immunology_Janeway. Caused by Plasmodium species, malaria is another serious and widespread disease. Like Trypanosoma brucei, Plasmodium species vary their antigens to avoid elimination by the immune system. In addition, plasmodia undergo different parts of their life cycle in different cellular hosts within humans. Initial infection is by the sporozoite form of the organism, which is transmitted by the bite of an infected mosquito and targets hepatocytes in the liver. Here, the organism replicates rapidly to produce merozoites that burst from infected hepatocytes to infect circulating red blood cells. Thus, as the immune system focuses it efforts on the eradication of the parasite in the liver, the parasite morphs and escapes to its second cellular host, red blood cells. And because red blood cells are the only cells in the body that lack MHC class I molecules, antigens produced by the merozoites within infected red blood cells escape detection by CD8 T cells, preventing cytotoxic destruction of the


Immunology_Janeway

Immunology_Janeway. only cells in the body that lack MHC class I molecules, antigens produced by the merozoites within infected red blood cells escape detection by CD8 T cells, preventing cytotoxic destruction of the infected cells. This represents one of the most elegant adaptations to evade cellmediated immunity.


Immunology_Janeway

Immunology_Janeway. Immune subversion is also practiced by protozoan parasites. Leishmania major, which is transmitted to dermal tissues of humans by the bite of sandflies, is an obligate intracellular parasite that replicates within tissue macrophages. As is true of other intracellular pathogens that reside within phagocytic vesicles, eradication of L. major is dependent on a type 1 immune response. Through mechanisms that are incompletely understood, L. major specifically inhibits the production of IL12 by its macrophage host, thereby inhibiting the production of IFNγ by NK cells and inhibiting the differentiation and function of TH1 cells. In addition, L. major has been shown to actively induce IL10producing Treg cells that suppress clearance of the infection. 13-22 RNA viruses use different mechanisms of antigenic variation to keep a step ahead of the adaptive immune system.


Immunology_Janeway

Immunology_Janeway. Viruses are both the simplest and most diverse of pathogens. They can replicate only within living cells, relying on host cellular machinery to replicate and propagate themselves. As obligate intracellular pathogens, they activate intracellular PRRs that sense viral genetic material and provoke cytolytic immune responses by innate and adaptive immune cells—NK cells and CD8 T cells, respectively. They also induce type I interferon responses, which activate cellintrinsic mechanisms to limit viral replication in both infected and uninfected cells. Although many cells produce type I interferons, plasmacytoid dendritic cells are innate sensor cells that are specialized for high levels of type I interferon production early in viral infections and, along with NK cells, play a central role in early antiviral host defense before the adaptive response matures. The latter involves all arms of adaptive immunity: induction of TH1 cells that provide help for production of opsonizing and


Immunology_Janeway

Immunology_Janeway. role in early antiviral host defense before the adaptive response matures. The latter involves all arms of adaptive immunity: induction of TH1 cells that provide help for production of opsonizing and complementfixing virusspecific antibodies that block viral entry into uninfected cells and activate complement to destroy enveloped viruses; and cytolytic CD8 T cells, which destroy virally infected cells and produce IFNγ.


Immunology_Janeway

Immunology_Janeway. The strategies used by viruses to defeat immune defenses are as varied as the pathogens themselves. However, some general strategies relate to the type of viral genome. RNA viruses must replicate their genomes using RNA polymerases, which lack the proofreading ability of DNA polymerase. A consequence of this is that RNA viruses have a greater rate of mutation than DNA viruses, with the practical consequence that RNA viruses cannot support large genomes. However, this also affords them opportunities for rapidly altering antigenic epitopes targeted by the adaptive immune system as a mechanism for immune evasion. Further, some RNA viruses have segmented genomes, which lend themselves to reassortment during viral replication. Both of these mechanisms are used by influenza virus, a common seasonal viral pathogen that causes acute infections and has been responsible for several major pandemics. At any one time, a single virus type is responsible for most cases of influenza throughout the


Immunology_Janeway

Immunology_Janeway. viral pathogen that causes acute infections and has been responsible for several major pandemics. At any one time, a single virus type is responsible for most cases of influenza throughout the world. The human population gradually develops protective immunity to this virus type, chiefly through the production of neutralizing antibody directed against the viral hemagglutinin, the main surface protein of the influenza virus. Because the virus is rapidly cleared from immune individuals, it might be in danger of running out of potential hosts were it not able to use both mutation mechanisms to alter its antigenic type (Fig. 13.22).


Immunology_Janeway

Immunology_Janeway. The first of these, caused by point mutations in the genes encoding the two major viral surface glycoproteins—hemagglutinin and neuraminidase—is called antigenic drift. Every 2–3 years a variant flu virus arises with mutations that allow it to evade neutralization by the antibodies present in the population. Other mutations may affect epitopes in viral proteins that are recognized by T cells, particularly CD8 cytotoxic T cells, with the consequence that cells infected with the mutant virus also escape destruction. People immune to the old flu virus are thus susceptible to the new variant, but because the changes in the viral proteins are relatively minor, there is still some crossreaction with antibodies and memory T cells produced against the previous variant, and most of the population still has some level of immunity. Thus, epidemics resulting from antigenic drift are typically mild.


Immunology_Janeway

Immunology_Janeway. Antigenic changes in influenza virus that result from reassortment of the segmented RNA genome are known as antigenic shift, and result in major changes in the hemagglutinin expressed by the virus. Antigenic shifts cause global pandemics of severe disease, often with substantial mortality, because the new hemagglutinin is recognized poorly, if at all, by antibodies and T cells


Immunology_Janeway

Immunology_Janeway. Fig. 13.22 Two types of variation allow repeated infection with type A influenza virus. neutralizing antibody that mediates protective immunity is directed at the viral surface protein hemagglutinin (H), which is responsible for viral binding to and entry into cells. antigenic drift (left panels) involves the emergence of point mutants with altered binding sites for protective antibodies on the hemagglutinin. the new virus can grow in a host that is immune to the previous strain of virus, but as t cells and some antibodies can still recognize epitopes that have not been altered, the new variants cause only mild disease in previously infected individuals. antigenic shift (right panels) is a rare event involving the reassortment of the segmented Rna viral genomes of two different influenza viruses, probably in a bird or a pig. these antigen-shifted viruses have large changes in their hemagglutinin, and therefore t cells and antibodies produced in earlier infections are not protective.


Immunology_Janeway

Immunology_Janeway. viruses, probably in a bird or a pig. these antigen-shifted viruses have large changes in their hemagglutinin, and therefore t cells and antibodies produced in earlier infections are not protective. these shifted strains cause severe infection that spreads widely, causing the influenza pandemics that occur every 10–50 years. there are eight Rna molecules in each viral genome, but for simplicity only three are shown.


Immunology_Janeway

Immunology_Janeway. directed against the previous variant. Antigenic shift is due to reassortment of the segmented RNA genome of the human influenza virus and animal influenza viruses in an animal host, in which the hemagglutinin gene from the animal virus replaces the hemagglutinin gene in the human virus (see Fig. 13.22).


Immunology_Janeway

Immunology_Janeway. Hepatitis C virus (HCV) is an RNA virus that can cause both acute and chronic infections of the liver. It is the most common cause of bloodborne chronic infection in the United States, and the leading viral cause of liver cirrhosis. As with influenza virus, HCV has a high capacity for mutation of immune epitopes that allow it to evade elimination. However, unlike influenza, the viral surface glycoprotein responsible for binding of HCV to hepatocytes (E2, which binds CD81) presents a difficult target against which to produce effective neutralizing antibodies, due both to its heavy glycosylation in the region of CD81 binding and its high rate of mutation. Antibody responses against HCV are therefore of limited effectiveness. Similarly, high rates of mutation of Tcell epitopes select for escape variants of HCV that evade cytolytic Tcell responses. Finally, there is evidence that HCV also expresses factors that subvert the function of dendritic cells, thereby impairing the induction of


Immunology_Janeway

Immunology_Janeway. variants of HCV that evade cytolytic Tcell responses. Finally, there is evidence that HCV also expresses factors that subvert the function of dendritic cells, thereby impairing the induction of Tcell immunity.


Immunology_Janeway

Immunology_Janeway. 13-23 DNA viruses use multiple mechanisms to subvert NK-cell and CTL responses.


Immunology_Janeway

Immunology_Janeway. Of all the pathogens, DNA viruses that can establish chronic infections have evolved the greatest diversity of mechanisms for subverting or escaping immune defenses. Unlike RNA viruses, DNA viruses have relatively low mutation rates and are thus less able to employ antigenic variation to evade immune defenses. However, because their lower rate of mutation allows them to support much larger genomes, these viruses have been able to accommodate a remarkable number of viral genes encoding proteins that can subvert nearly every aspect of antiviral defense. In the case of poxvirus, adenovirus, and especially herpesviruses, all of them large DNA viruses that will be our focus here, over 50% of the genome can be dedicated to immune evasionrelated genes. Further, some of these viruses, particularly the herpesviruses, have evolved mechanisms that allow them to enter a state known as latency, in which the virus is not actively replicated. In the latent state, the virus does not cause disease;


Immunology_Janeway

Immunology_Janeway. the herpesviruses, have evolved mechanisms that allow them to enter a state known as latency, in which the virus is not actively replicated. In the latent state, the virus does not cause disease; however, because no viral peptides are produced to load MHC class I molecules that signal the virus’s presence to cytolytic T cells, it cannot be eliminated, and can establish lifelong infections. As we will discuss in Section 1324, latent infections can be reactivated, resulting in recurrent illness. Of the eight types of herpesvirus that infect humans, at least one of the five most common types—herpes simplex virus (HSV)1 and 2 (both of which can cause labial and genital herpes), Epstein–Barr virus (EBV, which causes infectious mononucleosis), varicellazoster (which causes chickenpox and shingles), and cytomegalovirus (CMV)—infects nine out of ten people, and typically establishes lifelong latency. Here we highlight major mechanisms by which these viruses succeed (Fig. 13.23).


Immunology_Janeway

Immunology_Janeway. Central to the longterm survival of the DNA viruses is evasion of CTLs and NK cells. The presentation of viral peptides by MHC class I molecules at a cell surface signals CD8 T cells to kill the infected cell. Many of the large DNA viruses evade immune recognition by producing proteins called immunoevasins, which prevent the appearance of viral peptide:MHC class I complexes on the infected cell (Fig. 13.24). Indeed, at least one viral inhibitor of every key step in the processing and presentation of peptide:MHC class I complexes has been described. Some immunoevasins block peptide entry into the endoplasmic reticulum by targeting the TAP transporter (Fig. 13.25, left panel). Viral proteins can also prevent peptide:MHC complexes from reaching the cell surface by retaining MHC class I molecules in the endoplasmic reticulum (see Fig. 13.25, middle panel). Several viral proteins catalyze the degradation of newly synthesized MHC class I molecules by a process known as dislocation, which


Immunology_Janeway

Immunology_Janeway. in the endoplasmic reticulum (see Fig. 13.25, middle panel). Several viral proteins catalyze the degradation of newly synthesized MHC class I molecules by a process known as dislocation, which initiates the pathway normally used to degrade misfolded endoplasmic reticulum proteins by directing them back into the cytosol (Fig. 13.25, right panel). By preventing the formation of stably assembled/folded peptide:MHC class I complexes, these viral proteins divert the peptide:MHC class I complexes into the ERassociated degradation (ERAD) pathway for disposal. Through these multiple mechanisms, viral factors impair or completely block the presentation of viral peptides to CTLs. The actions of viral inhibitors are not limited to the MHC class I pathway, as viral inhibitors of the class II processing pathway have also been described; these inhibitors ultimately target CD4 T cells. Finally, as many viruses target cells other than dendritic cells, their antigens come to the attention of CD8 T


Immunology_Janeway

Immunology_Janeway. pathway have also been described; these inhibitors ultimately target CD4 T cells. Finally, as many viruses target cells other than dendritic cells, their antigens come to the attention of CD8 T cells via crosspresentation. Viral mechanisms that interfere with this pathway are not well described, although it is known that because the viruses are not required to persist in dendritic cells, the viruses can block recognition and destruction of their cellular hosts even after primed CTL effectors have been generated.


Immunology_Janeway

Immunology_Janeway. In addition to their role in the acute innate response to viral infection, a major function of NK cells is the recognition and cytolysis of cells that have downregulated MHC class I molecules as a foil to pathogen attempts to evade detection by CTLs. Accordingly, viruses that target the MHC class I pathway have also evolved mechanisms to repress the cytolytic activity of NK cells. Strategies here include, but are not limited to, expression of viral homologs of MHC class I that engage killer inhibitory receptors (KIRs) and leukocyte inhibitory receptors (LIRs). For example, human CMV produces a homolog of HLA class I called Fig. 13.24 Immunoevasins produced by viruses interfere with the processing of antigens that bind to MHC class I molecules. UL18, which binds LIR1 on NK cells and provides an inhibitory signal that blocks NKcell cytolysis. Viral products have been defined that also antagonize activating receptors on NK cells, as well as inhibit NKcell effector pathways.


Immunology_Janeway

Immunology_Janeway. DNA viruses have evolved mechanisms to subvert additional functions of the immune system. The mechanisms used include the expression of viral homologs of cytokines or chemokines and their receptors, or viral proteins


Immunology_Janeway

Immunology_Janeway. Fig. 13.25 The peptide-loading complex in the endoplasmic reticulum is targeted by viral immunoevasins. the left panel shows blockade of peptide entry to the endoplasmic reticulum (eR). the cytosolic iCP47 protein from herpes simplex virus (HSV)-1 prevents peptides from binding to taP in the cytosol, whereas the uS6 protein from human CMV interferes with the atP-dependent transfer of peptides through taP. the middle panel shows the retention of MHC class i molecules in the eR by the adenovirus e19 protein. this binds certain MHC molecules and retains them in the eR through an eR-retention motif, at the same time competing with tapasin to prevent association with taP and peptide loading. the right panel shows how the murine herpes virus mK3 protein, an e3ubiquitin ligase, targets newly synthesized MHC class i molecules. mK3 associates with tapasin:taP complexes and directs the addition of ubiquitin subunits with K48 linkages (see Section 7-5) to the cytoplasmic tail of the MHC class i


Immunology_Janeway

Immunology_Janeway. MHC class i molecules. mK3 associates with tapasin:taP complexes and directs the addition of ubiquitin subunits with K48 linkages (see Section 7-5) to the cytoplasmic tail of the MHC class i molecule. the polyubiquitination of the cytoplasmic tail of MHC initiates the process of degradation of the MHC molecule by the proteasomal pathway.


Immunology_Janeway

Immunology_Janeway. that bind cytokines or their receptors to inhibit their actions. As type I and II interferons are major effector cytokines in antiviral defense, diverse viral strategies are centered on the inhibition of this family of cytokines, whether by production of decoy receptors or inhibitory binding proteins, inhibition of JAK/STAT signaling by IFN receptors, inhibition of cytokine transcription, or interference with transcription factors induced by IFNs. Some DNA viruses also produce antagonists of the proinflammatory cytokines IL1, IL18, and TNFα, among others. Viral homologs of immunosuppressive cytokines are also produced. CMV impairs antiviral responses by producing a homolog of the cytokine IL10, called cmvIL10, which downregulates the production of several proinflammatory cytokines by immune cells, including IFNγ, IL12, IL1, and TNFα, to promote tolerogenic rather than immunogenic adaptive responses to viral antigens.


Immunology_Janeway

Immunology_Janeway. Several viruses also interfere with chemokine responses by producing either decoy chemokine receptors or chemokine homologs that interfere with natural ligandinduced signaling through chemokine receptors. Collectively, herpesviruses and poxviruses produce over 40 viral homologs of receptors belonging to the seven transmembranespanning Gproteincoupled chemokine receptor (vGPCR) superfamily. Finally, CMV has been shown to promote chronic infection that is associated with ‘exhaustion’ of antiviral CD8 T cells. CD8 T cells induced in this setting are characterized by expression of an inhibitory receptor of the CD28 superfamily, the programmed death1 (PD1) receptor (see Section 724), activation of which by its ligand PDL1 suppresses CD8 Tcell effector function. Blockade of the PDL1–PD1 interaction restores antiviral CD8 effector function and decreases the viral load, indicating that ongoing activation of this pathway is involved in impaired viral clearance. A similar mechanism has been


Immunology_Janeway

Immunology_Janeway. restores antiviral CD8 effector function and decreases the viral load, indicating that ongoing activation of this pathway is involved in impaired viral clearance. A similar mechanism has been implicated in RNA viruses that can establish chronic infections, such as hepatitis C virus (HCV). Suffice it to say that the range of strategies that viruses have evolved to subvert immune clearance mechanisms is quite remarkable, and the discovery of these mechanisms continues to have a major impact on our understanding of host–pathogen relationships.


Immunology_Janeway

Immunology_Janeway. 13-24 Some latent viruses persist in vivo by ceasing to replicate until immunity wanes.


Immunology_Janeway

Immunology_Janeway. As mentioned in the previous section, a major class of viral agents that cause latent infections in humans are the herpesviruses, large, enveloped DNA viruses that are characterized by their ability to establish lifelong infections. While we have considered a number of strategies by which these viruses subvert immunity, they have also evolved mechanisms to maintain their genome within the nucleus of infected cells indefinitely without replicating. In contrast to an actively lytic, or productive, phase of the viral life cycle, wherein the virus replicates and lyses its cellular host, herpesviruses can establish latency, or a lysogenic phase, by expression of a small region of their genome called the latency associated transcript (LAT). In addition to suppressing the transcription of the remaining viral genome, the LAT produces factors that interfere with apoptotic death of the host cell, both interfering with immune mechanisms that might clear the cell and prolonging the cell’s


Immunology_Janeway

Immunology_Janeway. the remaining viral genome, the LAT produces factors that interfere with apoptotic death of the host cell, both interfering with immune mechanisms that might clear the cell and prolonging the cell’s lifespan—and that of the viral genome it harbors. An example is herpes simplex virus (HSV), the cause of cold sores, which infects epithelial cells and then spreads to sensory neurons serving the infected area. An effective immune response controls the epithelial infection, but the virus persists in a latent state in the sensory neurons. Factors such as sunlight, bacterial infection, or hormonal changes reactivate the virus, which then travels down the axons of the sensory neuron and reinfects the epithelial tissues (Fig. 13.26). At this point, the immune response again becomes active and controls the local infection by killing the epithelial cells, producing a new sore. This cycle can be repeated many times.


Immunology_Janeway

Immunology_Janeway. Fig. 13.26 Persistence and reactivation of herpes simplex virus infection. the initial infection in the skin is cleared by an effective immune response, but residual infection persists in sensory neurons such as those of the trigeminal ganglion, whose axons innervate the lips. When the virus is reactivated, usually by some environmental stress and/or alteration in immune status, the skin in the area served by the nerve is reinfected from virus in the ganglion and a new cold sore results. this process can be repeated many times.


Immunology_Janeway

Immunology_Janeway. There are two reasons why the sensory neuron remains infected: first, the virus is quiescent and generates few virusderived peptides to present on MHC class I molecules; second, neurons carry very low levels of MHC class I molecules, which makes it harder for CD8 cytotoxic T cells to recognize infected neurons and attack them. The low level of MHC class I expression is beneficial because it reduces the risk that neurons, which have a limited capacity for regeneration, will be targeted inappropriately by cytotoxic T cells. It does, however, make neurons attractive as cellular reservoirs for persistent infections. Herpesviruses often enter latency. Herpes zoster (varicellazoster), which causes chickenpox, remains latent in one or a few dorsal root ganglia after the acute illness is over, and can be reactivated by stress or immunosuppression. It then spreads down the nerve and reinfects the skin to cause the disease herpes zoster, or shingles, which is marked by the reappearance of the


Immunology_Janeway

Immunology_Janeway. can be reactivated by stress or immunosuppression. It then spreads down the nerve and reinfects the skin to cause the disease herpes zoster, or shingles, which is marked by the reappearance of the classic varicella rash in the area of skin served by the infected dorsal root. Unlike herpes simplex, which reactivates frequently, herpes zoster usually reactivates only once in a lifetime in an immunocompetent host.


Immunology_Janeway

Immunology_Janeway. Yet another herpesvirus, the Epstein–Barr virus (EBV), establishes a persistent infection in most individuals. EBV enters latency in B cells after a primary infection that often passes without being diagnosed. In a minority of infected individuals, the initial acute infection of B cells is more severe, causing the disease known as infectious mononucleosis or glandular fever. EBV infects B cells by binding to CR2 (CD21), a component of the Bcell coreceptor complex, and to MHC class II molecules. In the primary infection, most of the infected cells proliferate and produce virus, leading in turn to the proliferation of antigenspecific T cells and the excess of mononuclear white cells in the blood that gives the disease its name. Virus is released from the B cells, destroying them in the process, and virus can be recovered from saliva. The infection is eventually controlled by virusspecific CD8 cytotoxic T cells, which kill the infected proliferating B cells. A fraction of memory B


Immunology_Janeway

Immunology_Janeway. process, and virus can be recovered from saliva. The infection is eventually controlled by virusspecific CD8 cytotoxic T cells, which kill the infected proliferating B cells. A fraction of memory B lymphocytes become latently infected, however, and EBV remains quiescent in these cells.


Immunology_Janeway

Immunology_Janeway. These two forms of infection are accompanied by quite different patterns of expression of viral genes. EBV has a large DNA genome encoding more than 70 proteins. Many of these are required for viral replication and are expressed by the replicating virus, providing a source of viral peptides by which infected cells can be recognized. In a latent infection, in contrast, the virus survives within the host B cells without replicating, and a very limited set of viral proteins is expressed. One of these is the Epstein–Barr nuclear antigen 1 (EBNA1), which is needed to maintain the viral genome. EBNA1 interacts with the proteasome (see Section 62) to prevent its own degradation into peptides that would otherwise elicit a Tcell response.


Immunology_Janeway

Immunology_Janeway. Latently infected B cells can be isolated by culturing B cells from individuals who have apparently cleared their EBV infection: in the absence of T cells, latently infected cells retaining the EBV genome become transformed into socalled immortal cell lines, the equivalent of tumorigenesis in vitro. Infected B cells occasionally undergo malignant transformation in vivo, giving rise to a Bcell lymphoma called Burkitt’s lymphoma. In this lymphoma, expression of the peptide transporters TAP1 and TAP2 is downregulated (see Section 63), and so cells are unable to process endogenous antigens for presentation on HLA class I molecules (the human MHC class I). This deficiency provides one explanation for how these tumors escape attack by CD8 cytotoxic T cells. Patients with acquired and inherited immunodeficiencies of Tcell function have an increased risk of developing EBVassociated lymphomas, presumably as a result of a failure of immune surveillance.


Immunology_Janeway

Immunology_Janeway. The viruses hepatitis B (HBV, a DNA virus) and hepatitis C (HCV, an RNA virus) infect the liver and cause acute and chronic hepatitis, liver cirrhosis, and in some cases hepatocellular carcinoma. Immune responses probably have an important role in the clearance of both types of hepatitis infection, but in many cases HBV and HCV set up a chronic infection. Although HCV mainly infects the liver during the early stage of a primary infection, the virus subverts the adaptive immune response by interfering with dendriticcell activation and maturation. This leads to inadequate activation of CD4 T cells and a consequent lack of TH1 cell differentiation, which is thought to be responsible for the infection becoming chronic, most probably because of the lack of CD4 Tcell help to activate naive CD8 cytotoxic T cells. There is evidence that the decrease in levels of viral antigen seen after antiviral treatment improves CD4 Tcell help and allows the restoration of cytotoxic CD8 Tcell function and


Immunology_Janeway

Immunology_Janeway. cytotoxic T cells. There is evidence that the decrease in levels of viral antigen seen after antiviral treatment improves CD4 Tcell help and allows the restoration of cytotoxic CD8 Tcell function and memory CD8 Tcell function. The delay in dendriticcell maturation caused by HCV is thought to synergize with another property of the virus that helps it to evade an immune response: the RNA polymerase that the virus uses to replicate its genome lacks proofreading capacity. This contributes to a high viral mutation rate and thus a change in its antigenicity, which allows it to evade adaptive immunity.


Immunology_Janeway

Immunology_Janeway. Summary. Infectious agents can cause recurrent or persistent disease by avoiding normal host defense mechanisms or by subverting them to promote their own replication. There are many different ways of evading or subverting the immune response. Antigenic variation, latency, resistance to immune effector mechanisms, and suppression of the immune response all contribute to persistent and medically important infections. In some cases the immune response is part of the problem: some pathogens use immune activation to spread infection, and others would not cause disease if it were not for the immune response. Each of these mechanisms teaches us something about the nature of the immune response and its weaknesses, and each requires a different medical approach to prevent or to treat infection. Acquired immune deficiency syndrome.


Immunology_Janeway

Immunology_Janeway. Acquired immune deficiency syndrome. The most extreme example of immune subversion by a pathogen is the acquired immune deficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV). The disease is characterized by a progressive loss of CD4 T cells, which, when they have become sufficiently depleted, results in high susceptibility to opportunistic infections and certain malignancies. The earliest documented case of HIV infection in humans to date was reported in a sample of serum from Kinshasa (Democratic Republic of the Congo) that was stored in 1959. It was not until 1981, however, that the first cases of AIDS were officially reported. Because the disease seemed to be spread by contact with body fluids, the cause was suspected to be a new virus, and by 1983 the causative agent, HIV, was isolated and identified.


Immunology_Janeway

Immunology_Janeway. There are at least two types of HIV—HIV1 and HIV2—that are closely related. While both types are transmitted by sexual contact and bloodborne exposure (for example, blood transfusion, shared needles), HIV1 replicates to higher viral loads in blood and is therefore more easily transmitted; HIV1 has a high rate of transmission from mother to child, which is uncommon in HIV2. Although disease is indistinguishable in patients who progress to AIDS, HIV1 progresses to AIDS more rapidly and with greater incidence than HIV2. HIV1 is therefore by far the most prevalent cause of AIDS worldwide. And while both HIV1 and HIV2 are endemic to West Africa, HIV2 is rarely found elsewhere. Both viruses seem to have originally spread to humans from other primate species in Africa. Viral genome sequencing of isolates suggests that the primate precursor of HIV1, simian immunodeficiency virus (SIV), has passed


Immunology_Janeway

Immunology_Janeway. Fig. 13.27 Phylogenetic origins of HIV-1 and HIV-2. HiV-1 shows marked genetic variability and is classified on the basis of genomic sequence into four major groups: M (main), O (outlier), n (non-M, non-O), and P (non-M, non-n, non-O), which are further diversified into subtypes, or clades, that are designated by the letters a to K. in different parts of the world, different subtypes predominate. Phylogenetic analyses of chimpanzee simian immunodeficiency virus (SiVcpz), gorilla SiV (SiVgor), and HiV-1 sequences demonstrate that the four groups of HiV-1 (M, n, O, and P) originated from four independent cross-species transmission events: two transfers of SiVcpzPtt from central chimpanzees (subspecies Pan troglodytes troglodytes, or Ptt) gave rise to HiV-1 groups M and n, while two transfers of SiVgor from western lowland gorillas (subspecies Gorilla gorilla gorilla) gave rise to HiV-1 groups O and P. Similarly, separate zoonotic transmissions of SiVsmm from sooty mangabey monkeys to


Immunology_Janeway

Immunology_Janeway. of SiVgor from western lowland gorillas (subspecies Gorilla gorilla gorilla) gave rise to HiV-1 groups O and P. Similarly, separate zoonotic transmissions of SiVsmm from sooty mangabey monkeys to humans are responsible for at least nine different lineages of HiV-2 (groups a–H and a newly described lineage, u). SiVstm and SiVmac resulted from experimental infections of stump-tailed macaques and rhesus macaques with SiVsmm, respectively. abbreviations: cpzPts, chimpanzee Pan troglodytes schweinfurthii; cpzPtt, chimpanzee Pan troglodytes troglodytes; mac, macaque; SiV, simian immunodeficiency virus; smm, sooty mangabey monkey; stm, stump-tailed macaque. Figure courtesy of Drs. Beatrice Hahn and Gerald learn.


Immunology_Janeway

Immunology_Janeway. to humans on at least four independent occasions from chimpanzees or western lowland gorillas, whereas HIV2 originated in the sooty mangabey (Fig. 13.27). The best estimate is that the most prevalent of the four major variants of HIV1, group M (responsible for ~99% of HIV1 infections worldwide), was transmitted to humans from chimpanzees in the first half of the twentieth century; transmission of group O also dates to the early twentieth century, whereas the two other HIV1 variants (groups N and P) appear to have been transmitted more recently. As is true for other zoonotic infections where there has been insufficient time for pathogen and host to coevolve to an equilibrium that attenuates virulence, SIV is generally less pathogenic in its nonhuman primate host than is HIV in its human host. Thus, whereas development of AIDS is nearly universal in HIV1infected humans that do not receive treatment, development of AIDS in SIVinfected nonhuman primates is considerably more variable, with


Immunology_Janeway

Immunology_Janeway. Thus, whereas development of AIDS is nearly universal in HIV1infected humans that do not receive treatment, development of AIDS in SIVinfected nonhuman primates is considerably more variable, with some primates failing to develop disease at all.


Immunology_Janeway

Immunology_Janeway. HIV infection does not immediately cause AIDS. Without treatment, the average time to development of AIDS following infection of adults is several years. The long delay between infection and development of symptomatic immune deficiency reflects the unusual tropism of the virus for CD4 T cells of the immune system, as well as the nature of the immune response to the virus. HIV is now pandemic, and despite great strides in treatment and prevention that have followed from a greater understanding of the pathogenesis and epidemiology of the disease, 1.6 million people died of AIDSrelated causes in 2012 and an estimated 35.3 million are infected by HIV worldwide, presaging the death of many from AIDS for years to come (Fig. 13.28). In subSaharan Africa, which accounts for over twothirds of the global incidence, 1 in every 20 adults is infected. Indeed, HIV/AIDS has emerged as the most deadly single infectious agent in the short time since its identification as a new human pathogen.


Immunology_Janeway

Immunology_Janeway. of the global incidence, 1 in every 20 adults is infected. Indeed, HIV/AIDS has emerged as the most deadly single infectious agent in the short time since its identification as a new human pathogen. Nevertheless, there is cause for optimism: the incidence of new cases of HIV infections worldwide has declined annually since its peak in 1997, and the number of annual deaths from HIV/AIDS has steadily declined since its peak in the mid2000s. Among the regions with the most rapid declines in incidence of new infections is subSaharan Africa. Still, there are focal areas of increasing incidence (for example, Eastern Europe and Central Asia).


Immunology_Janeway

Immunology_Janeway. 13-25 HIV is a retrovirus that establishes a chronic infection that slowly progresses to AIDS.


Immunology_Janeway

Immunology_Janeway. HIV is an enveloped RNA virus whose structure is shown in Fig. 13.29. Each virus particle, or virion, is decorated with two viral envelope proteins that are used by the virus to infect target cells, and contains two copies of an RNA genome and numerous copies of viral enzymes that are required to establish infection in the cellular host. HIV is an example of a retrovirus, so named because the viral genome must be transcribed from RNA into DNA in the infected cell—the reverse (retro) of the usual pattern of transcription—by the viral reverse transcriptase enzyme. This generates a DNA intermediate that is integrated into the hostcell chromosomes to enable viral replication. RNA transcripts produced from the integrated viral DNA serve both as mRNAs to direct the synthesis of viral proteins and later as the RNA genomes of new viral particles. These escape from the cell by budding from the plasma membrane, each enclosed in a membrane envelope.


Immunology_Janeway

Immunology_Janeway. Worldwide totals 35.3 million/2.3 million/1.6 million total cases in 2012 new cases in 2012 deaths in 2012 Sub-Saharan Africa 25 million/1.6 million/1.2 million Caribbean 250,000/12,000/11,000 South and South-east Asia 3.9 million/270,000/220,000 Latin America 1.5 million/86,000/52,000 Eastern Europe and Central Asia 1.3 million/130,000/91,000 East Asia 800,000/270,000/220,000 North America 1.3 million/48,000/20,000 Western Europe 860,000/29,000/17,000 North Africa and Middle East 260,000/32,000/17,000 Oceania 51,000/2100/1200 Fig. 13.28 The incidence of new HIV infection is increasing more slowly in many regions of the world, but AIDS is still a major disease burden. the number of individuals living with HiV/aiDS is large and continues to grow, but the number of new infections in 2012 decreased by over one-third since the peak of the epidemic. Worldwide, in 2012, it is estimated that there were around 35.3 million individuals infected with HiV, including some 2.4 million new cases,


Immunology_Janeway

Immunology_Janeway. by over one-third since the peak of the epidemic. Worldwide, in 2012, it is estimated that there were around 35.3 million individuals infected with HiV, including some 2.4 million new cases, and approximately 1.6 million deaths from aiDS, a decrease of 30% since the peak in 2005. new infections in children have declined approximately 50% since 2001, with 260,000 new cases in 2012. (AIDS Epidemic Update, unaiDS/World Health Organization, 2013.)


Immunology_Janeway

Immunology_Janeway. HIV belongs to a group of retroviruses called the lentiviruses, from the Latin lentus, meaning slow, because of the gradual course of the diseases that they cause. These viruses persist and continue to replicate for many years before causing overt signs of disease. In the case of HIV, the virus targets cells of the immune system itself, producing an initial acute infection that is controlled to the point that infection is not apparent, but rarely leading to an immune response that can prevent ongoing replication of the virus. Thus, although the initial acute infection does seem to be controlled by the immune system, HIV establishes latency within cells of the immune system and continues to replicate and infect new cells for many years. As will be discussed below, this ultimately exhausts the immune system, resulting in immune deficiency, or AIDS, that leads to opportunistic infections and/or malignancy that cause death.


Immunology_Janeway

Immunology_Janeway. Fig. 13.29 The virion of human immunodeficiency virus (HIV). the virus illustrated is HiV-1, the leading cause of aiDS. the virion is roughly spherical and measures 120 nm in diameter, or about 60 times smaller than the t cells it infects. the three viral enzymes that are packaged in the virion—reverse transcriptase, integrase, and protease—are shown schematically in the viral capsid. in reality, many molecules of these enzymes are contained in each virion. Photograph courtesy of H. Gelderblom. gp120env RNA genome envelope protease (p10) integrase (p32) nucleocapsid reverse transcriptase (p64) lipid membrane MHC proteins matrix proteins gp41 p17gag gp120/gp41 complex, or viral spike 13-26 HIV infects and replicates within cells of the immune system.


Immunology_Janeway

Immunology_Janeway. A defining characteristic of HIV is its ability to infect and replicate within activated cells of the immune system. Three immune cell types are the primary targets of HIV infection: CD4 T cells, macrophages, and dendritic cells. Of these, CD4 T cells support the great majority of viral replication. HIV’s ability to enter particular cell types, known as its cellular tropism, is determined by the expression of specific receptors for the virus on the surface of those cells. HIV enters cells by means of a complex of two noncovalently associated viral glycoproteins, gp120 and gp41, which form trimers in the viral envelope. The gp120 subunits of trimeric gp120/gp40 complexes bind with high affinity to the cellsurface molecule CD4, which is expressed on CD4 T cells, and to a lesser extent on subsets of dendritic cells and macrophages. Before fusion and entry of the virus, gp120 must also bind a coreceptor on the host cell. The major coreceptors are the chemokine receptors CCR5 and CXCR4.


Immunology_Janeway

Immunology_Janeway. subsets of dendritic cells and macrophages. Before fusion and entry of the virus, gp120 must also bind a coreceptor on the host cell. The major coreceptors are the chemokine receptors CCR5 and CXCR4. While CCR5 is predominantly expressed on subsets of effector memory CD4 T cells, dendritic cells, and macrophages, CXCR4 is expressed primarily by naive and central memory CD4 T cells. As we will discuss below, the particular chemokine coreceptor bound by a given viral particle is of importance in the transmission of HIV between individuals and its propagation within an infected person. After binding CD4, gp120 undergoes a conformational change that exposes a highaffinity site that is bound by the coreceptor. This, in turn, causes gp41 to unfold and insert a portion of its structure (fusion peptide) into the plasma membrane of the target cell, inducing fusion of the viral envelope with the cell’s plasma membrane. This allows the viral nucleocapsid, composed of the viral genome and


Immunology_Janeway

Immunology_Janeway. peptide) into the plasma membrane of the target cell, inducing fusion of the viral envelope with the cell’s plasma membrane. This allows the viral nucleocapsid, composed of the viral genome and associated viral proteins, to enter the hostcell cytoplasm (Fig. 13.30).


Immunology_Janeway

Immunology_Janeway. Once the virus has entered cells, it replicates similarly to other retroviruses. Reverse transcriptase transcribes the viral RNA into a complementary DNA (cDNA) copy. The viral cDNA, which encodes nine genes (Fig. 13.31), is then integrated into the hostcell genome by viral integrase, which recognizes and partially cleaves repetitive DNA sequences, called long terminal repeats (LTRs), that reside at each end of the viral genome. LTRs are required for the integration of the provirus into the hostcell DNA and contain binding sites for generegulatory proteins that control expression of the viral genes. The integrated cDNA copy is known as the provirus.


Immunology_Janeway

Immunology_Janeway. Like other retroviruses, the HIV genome is small, with three major genes— gag, pol, and env. The gag gene encodes the structural proteins of the viral nucleocapsid core, pol encodes the enzymes involved in viral replication, and env encodes the viral envelope glycoproteins. The gag and pol mRNAs are translated to give polyproteins—long polypeptide chains that are then cleaved by the viral protease (encoded by pol) into individual functional proteins. Thus, pol alone encodes the virion’s three major enzymes that are required for viral replication: reverse transcriptase, integrase, and viral protease. The product of the env gene, gp160, has to be cleaved by a hostcell protease into gp120 and gp41, which are then assembled as trimers in the viral envelope. HIV has six other, smaller, regulatory genes encoding proteins that affect viral replication and infectivity in various ways. Two of these, Tat and Rev, perform regulatory functions that are essential early in the viral replication


Immunology_Janeway

Immunology_Janeway. genes encoding proteins that affect viral replication and infectivity in various ways. Two of these, Tat and Rev, perform regulatory functions that are essential early in the viral replication cycle. The remaining four—Nef, Vif, Vpr, and Vpu—are essential for efficient virus production in vivo.


Immunology_Janeway

Immunology_Janeway. HIV can complete its replication cycle in the host cell to produce progeny virus, or, like other retroviruses and herpesviruses, establish a latent infection in which the provirus remains quiescent. What determines whether infection of a cell results in latency or a productive infection is unclear, but is thought to be related to the activation state of the cell infected. As we will discuss in the next section, transcription of the provirus following integration is initiated by host transcription factors, which are induced by immunecell activation.


Immunology_Janeway

Immunology_Janeway. Viral cDNA enters nucleus and is integrated into host DNA Reverse transcriptase copies viral RNA genomes into double-stranded cDNA Viral envelope fuses with cell membrane allowing viral genome to enter the cell Virus particle binds to CD4 and co-receptor on T cell nucleus CD4reverse transcriptase viral RNA genomegp41 gp120 viral cDNA provirus chromosomal DNA cytoplasm co-receptor cell membrane The late proteins Gag, Pol, and Env are translated and assembled into virus particles, which bud from the cell Tat ampliÿes transcription of viral RNA. Rev increases transport of singly spliced or unspliced viral RNA to cytoplasm RNA transcripts are multiply spliced, allowing translation of early genes tat and rev T-cell activation induces low-level transcription of provirus gp160PolGagTatNFB˜Rev


Immunology_Janeway

Immunology_Janeway. Fig. 13.30 The life cycle of HIV. top row: the virus binds to CD4 using gp120, which is altered by CD4 binding so that it now also binds a chemokine receptor that acts as a co-receptor for viral entry. this binding releases gp41, which causes fusion of the viral envelope with the cell membrane and release of the viral core into the cytoplasm. Once in the cytoplasm, the viral core releases the Rna genome, which is reverse-transcribed into double-stranded cDna using the viral reverse transcriptase. the double-stranded cDna migrates to the nucleus in association with the viral integrase and the Vpr protein and is integrated into the cell genome, becoming a provirus. Bottom row: activation of CD4 t cells induces the expression of the transcription factors nFκB and nFat, which bind to the proviral ltR and initiate transcription of the HiV genome. the first viral transcripts are extensively processed, producing spliced mRnas encoding several regulatory proteins, including tat and Rev. tat


Immunology_Janeway

Immunology_Janeway. ltR and initiate transcription of the HiV genome. the first viral transcripts are extensively processed, producing spliced mRnas encoding several regulatory proteins, including tat and Rev. tat both enhances transcription from the provirus and binds to the Rna transcripts, stabilizing them in a form that can be translated. Rev binds the Rna transcripts and transports them to the cytosol. as levels of Rev increase, less extensively spliced and unspliced viral transcripts are transported out of the nucleus. the singly spliced and unspliced transcripts encode the structural proteins of the virus, and unspliced transcripts, which are also the new viral genomes, are packaged with these proteins to form many new virus particles.


Immunology_Janeway

Immunology_Janeway. Thus, infection of a cell that becomes dormant soon after infection might favor viral latency, whereas infection of activated cells favors productive viral replication. This has important consequences in the case of CD4 T cells, which, unlike macrophages and dendritic cells, are very longlived and can provide a reservoir of latent HIV provirus that can be activated when the T cells are reactivated, even years after initial infection. Because macrophages and dendritic cells in tissues are shortlived cells that do not divide, latency in these


Immunology_Janeway

Immunology_Janeway. Fig. 13.31 The genomic organization of HIV. like all retroviruses, HiV-1 has an Rna genome flanked by long terminal repeats (ltRs) involved in viral integration and in regulation of transcription of the viral genome. the genome can be read in three frames, and several of the viral genes overlap in different reading frames. this allows the virus to encode many proteins in a small genome. the three main protein products—Gag, Pol, and env—are synthesized by all infectious retroviruses. the known functions of the different genes and their products are listed. the products of gag, pol, and env are known to be present in the mature viral particle, together with the viral Rna. the mRnas for tat, Rev, and nef proteins are produced by splicing of viral transcripts, so their genes are split in the viral genome. in the case of nef, only one exon, shown in yellow, is translated.


Immunology_Janeway

Immunology_Janeway. Gene product/function Group-speciÿc antigen gag pol env tat rev vif Polymerase Envelope Transactivator Regulator of viral expression Viral infectivity vpr Viral protein R vpu Viral protein U nef Negative-regulation factor Gene pol env tat LTR LTR gag Core proteins and matrix proteins Reverse transcriptase, protease, and integrase enzymes Transmembrane glycoproteins. gp120 binds CD4 and CCR5; gp41 is required for virus fusion and internalization Positive regulator of transcription Allows export of unspliced and partially spliced transcripts from nucleus Affects particle infectivity Transport of DNA to nucleus. Augments virion production. Cell-cycle arrest Promotes intracellular degradation of CD4 and enhances release of virus from cell membrane Augments viral replication in vivo and in vitro. Decreases CD4, MHC class I and II expression nefrev tat rev vif vpr vpu host cells would be shortlived. Thus, longlived latency of HIV is primarily a consequence of the tropism of the virus for


Immunology_Janeway

Immunology_Janeway. Decreases CD4, MHC class I and II expression nefrev tat rev vif vpr vpu host cells would be shortlived. Thus, longlived latency of HIV is primarily a consequence of the tropism of the virus for CD4 T cells. The combined features of tropism for CD4 T cells and activationdependent transcription of the provirus are central to the pathogenesis of HIV and its characteristic progressive depletion of CD4 T cells that leads to AIDS.


Immunology_Janeway

Immunology_Janeway. 13-27 Activated CD4 T cells are the major source of HIV replication.


Immunology_Janeway

Immunology_Janeway. HIV provirus requires activation of the host cell to complete its replication cycle and produce infectious virions that can infect other cells. This is due to a requirement for transactivation of proviral gene expression by transcription factors of the host cell. Two host transcription factors can initiate transcription of the viral genome: NFκB and NFAT. Both of these factors require cellular activation for their translocation to the nucleus, where they bind DNA and induce gene transcription (see Sections 714 and 716). While NFκB is expressed in all of the immune cells infected by HIV, NFAT is primarily activated in CD4 T cells, enabling transactivation of the provirus by an additional factor in this cell host. This, coupled with the fact that CD4 T cells are longlived and abundant in immune tissues, contributes to CD4 T cells being the major cellular source for HIV replication. Here we consider the mechanism by which transcription of the HIV provirus is regulated in CD4 T cells.


Immunology_Janeway

Immunology_Janeway. As discussed in Sections 714 and 716, activation of T cells by antigen induces activation and nuclear translocation of NFAT and NFκB; activation of effectormemory T cells by cytokines can also activate NFκB in the absence of antigen (Section 1112). Thus, in addition to antigendependent activation of HIV provirus transcription by NFAT and NFκB, provirus might be activated independently of Tcell receptor stimulation in memory CD4 T cells via NFκB alone, as it is in infected macrophages and dendritic cells. Binding of NFAT and NFκB initiates transcription of viral RNA by binding to promoters in the proviral LTR. The viral transcript is spliced in various ways to produce mRNAs for translation of viral proteins (see Fig. 13.26).


Immunology_Janeway

Immunology_Janeway. At least two of the viral proteins—Tat and Rev—serve to enhance production of the viral genome (see Fig. 13.30). Tat binds to a transcriptional activation region (TAR) in the 5ʹ LTR. This recruits cellular cyclin T1 and its partner, cyclindependent kinase 9 (CDK9), to form a complex that phosphorylates RNA polymerase and enhances its ability to generate fulllength transcripts of the viral genome. In this way, Tat provides a positive feedback circuit for amplification of productive viral replication. Rev is important for shuttling unspliced viral RNA transcripts out of the nucleus by binding to a specific viral RNA sequence, the Rev response element (RRE). Eukaryotic cells have mechanisms to prevent the export from the cell nucleus of incompletely spliced mRNA transcripts. This could pose a problem for the retrovirus, which is dependent on export of unspliced mRNA species that encode the full complement of viral proteins, as well as the viral RNA genome. While export of a fully spliced


Immunology_Janeway

Immunology_Janeway. problem for the retrovirus, which is dependent on export of unspliced mRNA species that encode the full complement of viral proteins, as well as the viral RNA genome. While export of a fully spliced mRNA transcript that encodes Tat and Rev occurs early after viral infection by means of the normal host cellular mechanisms of mRNA export, the export of later, unspliced viral transcripts requires Rev to prevent their destruction by the host cell.


Immunology_Janeway

Immunology_Janeway. The success of viral replication also depends on the proteins Nef, Vif, Vpu, and Vpr. These viral products appear to have evolved to defeat host immune mechanisms of viral clearance, as well as antiviral restriction factors—host cellular proteins that function in a cellautonomous manner to inhibit replication of retroviruses. Nef (negative regulation factor) performs multiple critical functions in the viral life cycle. It acts early in the viral life cycle to sustain Tcell activation and the establishment of a persistent state of HIV infection, in part by lowering the threshold for Tcell receptor signaling and downregulating expression of the inhibitory costimulatory receptor CTLA4. Combined, these actions result in greater and more sustained Tcell activation that promotes viral replication. Nef also contributes to immune evasion of infected cells by downregulating expression of MHC class I and class II molecules, making actively infected cells less likely to induce an antiviral


Immunology_Janeway

Immunology_Janeway. Nef also contributes to immune evasion of infected cells by downregulating expression of MHC class I and class II molecules, making actively infected cells less likely to induce an antiviral immune response or be killed by cytotoxic T cells. Nef also promotes the clearance of surface CD4 molecules, which otherwise would bind to the virion during budding and interfere with virion release. Vif (viral infectivity factor) acts to overcome a cytidine deaminase called APOBEC, which catalyzes the conversion of deoxycytidine to deoxyuridine in reversetranscribed viral cDNA, thereby destroying its ability to encode viral proteins. Vpu (viral protein U) is unique to HIV1 and variants of SIV, and is required to overcome a cellular factor called tetherin, which inserts into both the plasma membrane of the host cell and the envelope of the mature virion to block its release. The function of Vpr (viral protein R) is not fully understood, but it appears to target the restriction factor SAMHD1, a


Immunology_Janeway

Immunology_Janeway. of the host cell and the envelope of the mature virion to block its release. The function of Vpr (viral protein R) is not fully understood, but it appears to target the restriction factor SAMHD1, a cellular protein that inhibits HIV1 infection in myeloid cells and quiescent CD4 T cells by limiting the intracellular pool of deoxynucleotides (dNTPs) available for viral cDNA synthesis by reverse transcriptase.


Immunology_Janeway

Immunology_Janeway. 13-28 There are several routes by which HIV is transmitted and establishes infection. Infection with HIV occurs after the transfer of body fluids from an infected person to an uninfected one. HIV infection is most commonly spread by sexual intercourse. Transmission by the exchange of contaminated needles used for intravenous drug delivery or by the therapeutic use of infected blood or blood products also occurs, although the latter route of transmission has largely been eliminated in countries where blood products are routinely screened for HIV. An important route of virus transmission is from an infected mother to child, which can occur in utero, during birth, or through breast milk. Rates of transmission from an untreated infected mother to her child vary (from about 15% to 45%), depending on the viral load in the mother and whether the mother breastfeeds the child, as breastfeeding increases the risk of transmission.


Immunology_Janeway

Immunology_Janeway. The use of antiretroviral drugs to decrease maternal viral load during pregnancy dramatically reduces the transmission rate to the child (see Section 1335).


Immunology_Janeway

Immunology_Janeway. The virus can be transmitted as free infectious particles or via infected cells for which the virus has tropism (for example, CD4 T cells and macrophages). Infected cells are found in blood, but can also be present in semen or vaginal secretions, as well as breast milk; free virus is present in blood, semen, vaginal fluid, or mother’s milk. As we discuss in the next section, HIV virions can differentially express gp120 variants that bind either CCR5 or CXCR4, thereby influencing the cell types infected. In the genital and gastrointestinal mucosae, which are the dominant sites of primary infection by sexual transmission, HIV virions establish infection initially in a small number of mucosal immune cells that express CCR5—effector memory CD4 T cells, dendritic cells, and macrophages. The virus replicates locally in these cells before spreading via T cells or dendritic cells (mucosal macrophages are nonmigratory) to lymph nodes draining the mucosa. The lymphoid compartment of mucosal


Immunology_Janeway

Immunology_Janeway. virus replicates locally in these cells before spreading via T cells or dendritic cells (mucosal macrophages are nonmigratory) to lymph nodes draining the mucosa. The lymphoid compartment of mucosal tissues is enriched for TH1 and TH17 cells, which express CCR5 (naive T cells and TH2 cells do not), so initial viral replication is favored in these subsets of CD4 T cells. After accelerated replication in regional lymph nodes, where there is a high concentration of CD4 T cells, the virus disseminates widely via the bloodstream, and gains broader access to the gutassociated lymphoid tissues (GALT), where the highest number of CD4 T cells in the body reside.


Immunology_Janeway

Immunology_Janeway. 13-29 HIV variants with tropism for different co-receptors play different roles in transmission and progression of disease. To establish infection in a new host, HIV must make contact with a CD4expressing immune cell. The cell type targeted is determined by the affinity of viral gp120 for the different chemokine coreceptors: CCR5 or CXCR4. Accordingly, the two major tropism variants of HIV are referred to as ‘R5’ and ‘X4,’ respectively. Because CCR5 dominates on CD4expressing immune cells resident at the major sites of viral transmission—sites that are constantly exposed to commensal microbes and thus harbor large numbers of activated immune cells (mucosal tissues of the female and male genital tracts or rectum for sexual transmission; upper gastrointestinal tract for mothertochild transmission)—CCR5tropic R5 strains of virus are typically required for transmission, and dominate early in infection.


Immunology_Janeway

Immunology_Janeway. Before HIV can contact CD4expressing immune cells in the genital and intestinal mucosae, it must traverse the epithelium of these tissues. Here, the CCR5tropic variants of the virus also have an advantage. Infection occurs across two types of epithelium: the stratified, or multilayered, squamous epithelium that lines the mucosae of the vagina, foreskin of the penis, ectocervix, rectum, oropharynx, and esophagus; or the singlelayered columnar epithelium lining endocervix, rectum, and upper GI tract. Epithelial cells of the rectum and endocervix can express CCR5 and have been shown to selectively translocate R5, but not X4, HIV variants through the epithelial monolayer. Other molecules expressed by epithelial cells also participate; gp120binding glycosphingolipids expressed by epithelial cells of the vaginal or ectocervical mucosae also foster transcytosis of virus across the epithelium. The rate at which virus can transit epithelial barriers to establish infection is fast. SIV virus


Immunology_Janeway

Immunology_Janeway. cells of the vaginal or ectocervical mucosae also foster transcytosis of virus across the epithelium. The rate at which virus can transit epithelial barriers to establish infection is fast. SIV virus has been shown to penetrate the cervicovaginal epithelium within 30 to 60 minutes of exposure.


Immunology_Janeway

Immunology_Janeway. In addition to direct transcytosis across epithelial cells, the interdigitating processes of dendritic cells that ramify between epithelial cells provide an avenue for HIV to traverse the epithelium. A complex ferrying mechanism seems to transfer HIV picked up by dendritic cells to CD4 T cells in lymphoid tissue. HIV can attach to dendritic cells by the binding of viral gp120 to Ctype lectin receptors such as langerin (CD207), the mannose receptor (CD206), and DCSIGN. A portion of the bound virus is rapidly taken up into vacuoles, where it can remain for days in an infectious state. In this way the virus is protected and remains stable until it encounters a susceptible CD4 T cell, whether in the local mucosal environment or after being carried to draining lymphoid tissue (Fig. 13.32). Finally, at some mucosal sites, CCR5expressing CD4 T cells reside within the epithelium (intraepithelial T cells), and have been shown to be sites of early viral replication. Thus, HIV can infect CD4 T


Immunology_Janeway

Immunology_Janeway. at some mucosal sites, CCR5expressing CD4 T cells reside within the epithelium (intraepithelial T cells), and have been shown to be sites of early viral replication. Thus, HIV can infect CD4 T cells either directly or via dendritic cells that interact with CD4 T cells.


Immunology_Janeway

Immunology_Janeway. HIV is internalized into early endosomes Dendritic cells that have migrated to lymph nodes transfer HIV to CD4 T cells Intraepithelial dendritic cells bind HIV using DC-SIGN Fig. 13.32 Dendritic cells can initiate infection by transporting HIV from mucosal surfaces to lymphoid tissue. During the acute phase of infection, which typically lasts for several weeks and is characterized by an influenzalike illness, there is rapid replication of the virus, primarily in CCR5expressing CD4 T cells (Fig. 13.33). This period is marked by an abundance of virus circulating in the blood (viremia) and the rapid decline of CCR5expressing CD4 T cells, the latter due primarily to the


Immunology_Janeway

Immunology_Janeway. HiV adheres to the surface of intraepithelial dendritic cells by the binding of viral gp120 to DC-SiGn (left panel). it gains access to dendritic cells at sites of mucosal injury or possibly to dendritic cells that have protruded between epithelial cells to sample the external world; HiV can also bind directly to some epithelial cells and is transported across them to subepithelial dendritic cells (not shown). Dendritic cells internalize HiV virions into mildly acidic early endosomes and migrate to lymphoid tissue (center panel). HiV virions are translocated back to the cell surface, and when the dendritic cell encounters CD4 t cells in a secondary lymphoid tissue, the HiV is transferred to the t cell (right panel).


Immunology_Janeway

Immunology_Janeway. Fig. 13.33 The typical course of untreated infection with HIV. other symptoms become more frequent as the CD4 t-cell count in the first few weeks are typified by an acute influenza-like viral illness, peripheral blood falls, starting at about 500 cells · μl–1. the disease sometimes called seroconversion disease, with high titers of virus in then enters the symptomatic phase. When CD4 t-cell counts fall the blood. an adaptive immune response follows, which controls the below 200 cells · μl–1, the patient is said to have aiDS. note that acute illness and largely restores levels of CD4 t cells but does not CD4 t-cell counts are measured for clinical purposes in cells per eradicate the virus. this is the asymptomatic phase, which typically microliter (cells · μl–1), rather than cells per milliliter (cells · ml–1), the lasts 5–10 years without treatment. Opportunistic infections and unit used elsewhere in this book.


Immunology_Janeway

Immunology_Janeway. extensive death of CD4 T cells in the GALT that are killed by viral cytopathic effects (macrophages and dendritic cells appear more resistant to lysis by replicating virus). The depletion of immune cells in the gut might compound the rapid production of virus in the GALT by fostering increased immunecell activation due to barrier breakdown and translocation of constituents of the microbiota. Because of the high viral titers and preponderance of R5 strains during the acute phase of infection, the risk of viral transmission to uninfected contacts during this time is especially high.


Immunology_Janeway

Immunology_Janeway. The acute phase and its high viremia reside in virtually all patients once an adaptive immune response is established (see Fig. 13.33). Cytolytic CD8 T cells specific for viral antigens develop and kill HIVinfected cells, and virusspecific antibodies become detectable in the serum of those infected (seroconversion). The development of a CTL response results in early control of the virus, resulting in a sharp drop in viral titers and a rebound of CD4 Tcell counts. The level of virus that persists in blood plasma at this stage of infection, referred to as the viral set point, is usually a good indicator of future disease progression. At this point, the disease transitions to a clinically latent, or asymptomatic, phase marked by low viremia and slowly declining CD4 Tcell numbers, typically over several years. During this time the virus continues to actively replicate, but it is held in check, principally by HIVspecific CD8 T cells and antibodies.


Immunology_Janeway

Immunology_Janeway. Under strong selective pressure brought by the antiviral immune response, there is selection for HIV escape mutants that are no longer detected by adaptive immune cells. This gives rise to many different viral variants in a single infected person and to even broader variation within the population as a whole. Late in infection, in approximately 50% of cases, the dominant viral type switches from R5 to X4 variants that infect T cells via CXCR4 coreceptors. This is followed by a rapid decline in CD4 Tcell count and progression to AIDS. The exact mechanism by which this shift in viral tropism leads to accelerated loss of CD4 T cells is unknown. On balance, then, R5 variants appear critical for transmission of the virus from infected to uninfected individuals, whereas X4 variants that emerge under selective pressure exerted by the antiviral immune response contribute to the progression of disease within an infected individual.


Immunology_Janeway

Immunology_Janeway. 13-30 A genetic deficiency of the co-receptor CCR5 confers resistance to HIV infection.


Immunology_Janeway

Immunology_Janeway. Evidence for the importance of CCR5 in transmission of HIV infection has come from studies of individuals with a high risk of exposure to HIV1 who remain seronegative. Lymphocytes and macrophages from these people are resistant to HIV infection in cultures inoculated with HIV. The resistance of these individuals to HIV infection is explained by discovery that they are homozygous for a nonfunctional variant of CCR5 called Δ32, caused by a 32basepair deletion from the coding region that leads to a frameshift mutation and a truncated protein. The frequency of this mutant allele in Caucasians is high at 0.09 (that is, about 10% of the population are heterozygous carriers of the allele and about 1% are homozygous). The mutant allele has not been found in Japanese or in black Africans from Western or Central Africa. Whether heterozygous deficiency of CCR5 provides some protection against infection by HIV is controversial, but it appears to contribute to a modest, if any, reduction in


Immunology_Janeway

Immunology_Janeway. Western or Central Africa. Whether heterozygous deficiency of CCR5 provides some protection against infection by HIV is controversial, but it appears to contribute to a modest, if any, reduction in progression rates. In addition to the structural polymorphism of the gene, variations in the promoter region of the CCR5 gene have been associated with different rates of disease progression. The high incidence of the CCR5Δ32 allele in Caucasians predating the HIV pandemic suggests selection for this variant in a past epidemic. Both smallpox and bubonic plague have been put forward as possible selective agents, but this is as yet unproven.


Immunology_Janeway

Immunology_Janeway. 13-31 An immune response controls but does not eliminate HIV.


Immunology_Janeway

Immunology_Janeway. Infection with HIV generates an immune response that contains the virus but only very rarely, if ever, eliminates it. A timecourse of the response of various adaptive immune elements to HIV in adults is shown, together with the levels of infectious virus in plasma, in Fig. 13.34. As was noted earlier, in the acute phase, virusmediated cytopathicity results in a substantial depletion of CD4 T cells, particularly in mucosal tissues. There is a good initial recovery of Tcell numbers and transition to the asymptomatic phase of disease as the immune response develops and curbs viral replication (see Fig. 13.33). However, replication of the virus persists, and, after a variable period lasting from a few months to more than 20 years, the CD4 Tcell numbers fall too low to maintain effective immunity, and AIDS develops (defined as less than 200 CD4 T cells per microliter in peripheral blood). Several factors conspire to progressively deplete CD4 T cells until they can no longer maintain


Immunology_Janeway

Immunology_Janeway. immunity, and AIDS develops (defined as less than 200 CD4 T cells per microliter in peripheral blood). Several factors conspire to progressively deplete CD4 T cells until they can no longer maintain immunity: destruction by cytotoxic lymphocytes directed against HIVinfected cells, immune activation (direct and indirect) that induces activation of latent virus, ongoing viral cytopathic effects, and insufficient Tcell regeneration in the thymus. In this section we consider in turn the roles of CD8 cytotoxic T cells, CD4 T cells, antibodies, and soluble factors in mounting the immune response to HIV infection that initially contains the infection but ultimately fails.


Immunology_Janeway

Immunology_Janeway. Studies of peripheral blood cells from infected individuals reveal cytotoxic T cells specific for viral peptides that can kill infected cells in vitro. In vivo, cytotoxic T cells traffic to sites of HIV replication, where they are thought to kill many productively infected cells before any infectious virus is released, thereby containing viral load at the quasistable levels that are characteristic of the asymptomatic period. Evidence for the clinical importance of the control of HIVinfected cells by CD8 cytotoxic T cells comes from studies relating the numbers and activity of CD8 T cells to viral load. There is also direct evidence from experiments in macaques infected with SIV that CD8 cytotoxic T cells control retrovirusinfected cells; treatment of infected animals with monoclonal antibodies that remove CD8 T cells is rapidly followed by a large increase in viral load.


Immunology_Janeway

Immunology_Janeway. In addition to direct cytotoxicity mediated by recognition of cells infected with virus, a variety of factors produced by CD4, CD8, and NK cells are important in antiviral immunity. Chemokines that bind CCR5, such as CCL5, CCL3, and CCL4, are released at the site of infection by CD8 T cells and inhibit virus spread by competing with R5 strains of HIV1 for the engagement of coreceptor CCR5, whereas factors still unknown compete with R4 strains for binding to CXCR4. Cytokines such as IFNα and IFNγ may also be involved in controlling virus spread. 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.