392 PART I The Immune System in Health and Disease adoptive transfer: adoptive transfer of a Ctl clone specific these newly emerging strains leads to repeated epidemics of for influenza virus strain X protects mice against influenza influenza Antigenic variation among rhinoviruses, the causa- virus X but not against influenza virus strain. tive agent of the common cold, is responsible for our inabil ity to produce an effective vaccine for colds. Nowhere is anti- Viruses can evade host defense genic variation greater than in the human immunodeficiency echanisms virus(HIv), the causative agent of AIDS. Estimates suggest that hiv accumulates mutations at a rate 65 times faster thal Despite their restricted genome size, a number of viruses does influenza virus. Because of the importance of AIDS, have been found to encode proteins that interfere at various section of Chapter 19 addresses this disease levels with specific or nonspecific host defenses. Presumably, A large number of viruses evade the immune response by the advantage of such proteins is that they enable viruses to causing generalized immunosuppression. among these are replicate more effectively amidst host antiviral defenses. As he paramyxoviruses that cause mumps, the measles virus, described above, the induction of IFN-a and IFN-B is a Epstein-Barr virus(EBV), cytomegalovirus, and HIV. In major innate defense against viral infection, but some viruses some cases, immunosuppression is caused by direct viral in- have developed strategies to evade the action of IFN-a fection of lymphocytes or macrophages. The virus can then These include hepatitis C virus, which has been shown to either directly destroy the immune cells by cytolytic mecha- overcome the antiviral effect of the interferons by blocking or nisms or alter their function. In other cases, immunosup- inhibiting the action of PKR (see Figure 17-2) pression is the result of a cytokine imbalance. For example, Another mechanism for evading host responses, utilized BV produces a protein, called BCRFl, that is homologous to in particular by herpes simplex viruses(hsv) is inhibition IL-10: like IL-10, BCRFl suppresses cytokine production by of antigen presentation by infected host cells. HSV-1 and the TH1 subset, resulting in decreased levels of IL-2,TNE, and HSV-2 both express an immediate-early protein(a protein IFN-Y synthesized shortly after viral replication) called ICP47, which very effectively inhibits the human transporter mole- Influenza Has Been Responsible for Some cule needed for antigen processing(TAP; see Figure 8-8) of the Worst pandemics in histor Inhibition of TAP blocks antigen delivery to class I MHC re ceptors on HSV-infected cells, thus preventing presentation The influenza virus infects the upper respiratory tract and of viral antigen to CD8* T cells. This results in the trapping major central airways in humans, horses, birds, pigs, and of empty class I MHC molecules in the endoplasmic reticu- even seals In 1918-19, an influenza pandemic(worldwide lum and effectively shuts down a CD8 T-cell response to epidemic)killed more than 20 million people, a toll surpass- HSV-infected cells ing the number of casualties in World War I. Some areas, The targeting of MHC molecules is not unique to HSV. such as Alaska and the Pacific Islands. lost more than half of Other viruses have been shown to down-regulate class I their population during that pandemic MHC expression shortly after infection. Two of the best characterized examples, the adenoviruses and cytomegalo virus(CMv), use distinct molecular mechanisms to reduce PROPERTIES OF THE INFLUENZA VIRUS the surface expression of class I MHC molecules, again in- Influenza viral particles, or virions, are roughly spherical or hibiting antigen presentation to CD8 T cells. Some viruses- ovoid in shape, with an average diameter of 90-100 nm. The CMV, measles virus, and Hiv-have been shown to reduce virions are surrounded by an outer envelope-a lipid bilayer levels of class II MHC molecules on the cell surface, thus acquired from the plasma membrane of the infected host cell blocking the function of antigen-specific antiviral helper during the process of budding Inserted into the envelope are T cells two glycoproteins, hemagglutinin(HA)and neuraminidase Antibody-mediated destruction of viruses requires com- (NA), which form radiating projections that are visible in plement activation, resulting either in direct lysis of the vin electron micrographs(Figure 17-3). The hemagglutinin pro- particle or opsonization and elimination of the virus by jections, in the form of trimers, are responsible for the phagocytic cells. A number of viruses have strategies for evad- attachment of the virus to host cells. There are approximately ing complement-mediated destruction. Vaccinia virus, for 1000 hemagglutinin projections per influenza virion. The example, secretes a protein that binds to the CAb complement hemagglutinin trimer binds to sialic acid groups on host-cell component, inhibiting the classical complement pathway, glycoproteins and glycolipids by way of a conserved amino and herpes simplex viruses have a glycoprotein component acid sequence that forms a small groove in the hemagglu that binds to the C3b complement component, inhibiting tinin molecule Neuraminidase, as its name indicates, cleaves both the classical and alternative pathways N-acetylneuraminic(sialic)acid from nascent viral glyco- a number of viruses escape immune attack by constantly proteins and host-cell membrane glycoproteins, an activity langing their antigens. In the influenza virus, continual that presumably facilitates viral budding from the infected antigenic variation results in the frequent emergence of new host cell. Within the envelope, an inner layer of matrix pro- infectious strains. The absence of protective immunity to tein surrounds the nucleocapsid, which consists of eight dif-adoptive transfer: adoptive transfer of a CTL clone specific for influenza virus strain X protects mice against influenza virus X but not against influenza virus strain Y. Viruses Can Evade Host Defense Mechanisms Despite their restricted genome size, a number of viruses have been found to encode proteins that interfere at various levels with specific or nonspecific host defenses. Presumably, the advantage of such proteins is that they enable viruses to replicate more effectively amidst host antiviral defenses. As described above, the induction of IFN- and IFN- is a major innate defense against viral infection, but some viruses have developed strategies to evade the action of IFN-/. These include hepatitis C virus, which has been shown to overcome the antiviral effect of the interferons by blocking or inhibiting the action of PKR (see Figure 17-2). Another mechanism for evading host responses, utilized in particular by herpes simplex viruses (HSV) is inhibition of antigen presentation by infected host cells. HSV-1 and HSV-2 both express an immediate-early protein (a protein synthesized shortly after viral replication) called ICP47, which very effectively inhibits the human transporter mole￾cule needed for antigen processing (TAP; see Figure 8-8). Inhibition of TAP blocks antigen delivery to class I MHC re￾ceptors on HSV-infected cells, thus preventing presentation of viral antigen to CD8+ T cells. This results in the trapping of empty class I MHC molecules in the endoplasmic reticu￾lum and effectively shuts down a CD8+ T-cell response to HSV-infected cells. The targeting of MHC molecules is not unique to HSV. Other viruses have been shown to down-regulate class I MHC expression shortly after infection. Two of the best￾characterized examples, the adenoviruses and cytomegalo￾virus (CMV), use distinct molecular mechanisms to reduce the surface expression of class I MHC molecules, again in￾hibiting antigen presentation to CD8+ T cells. Some viruses— CMV, measles virus, and HIV—have been shown to reduce levels of class II MHC molecules on the cell surface, thus blocking the function of antigen-specific antiviral helper T cells. Antibody-mediated destruction of viruses requires com￾plement activation, resulting either in direct lysis of the viral particle or opsonization and elimination of the virus by phagocytic cells. A number of viruses have strategies for evad￾ing complement-mediated destruction. Vaccinia virus, for example, secretes a protein that binds to the C4b complement component, inhibiting the classical complement pathway; and herpes simplex viruses have a glycoprotein component that binds to the C3b complement component, inhibiting both the classical and alternative pathways. A number of viruses escape immune attack by constantly changing their antigens. In the influenza virus, continual antigenic variation results in the frequent emergence of new infectious strains. The absence of protective immunity to these newly emerging strains leads to repeated epidemics of influenza. Antigenic variation among rhinoviruses, the causa￾tive agent of the common cold, is responsible for our inabil￾ity to produce an effective vaccine for colds. Nowhere is anti￾genic variation greater than in the human immunodeficiency virus (HIV), the causative agent of AIDS. Estimates suggest that HIV accumulates mutations at a rate 65 times faster than does influenza virus. Because of the importance of AIDS, a section of Chapter 19 addresses this disease. A large number of viruses evade the immune response by causing generalized immunosuppression. Among these are the paramyxoviruses that cause mumps, the measles virus, Epstein-Barr virus (EBV), cytomegalovirus, and HIV. In some cases, immunosuppression is caused by direct viral in￾fection of lymphocytes or macrophages. The virus can then either directly destroy the immune cells by cytolytic mecha￾nisms or alter their function. In other cases, immunosup￾pression is the result of a cytokine imbalance. For example, EBV produces a protein, called BCRF1, that is homologous to IL-10; like IL-10, BCRF1 suppresses cytokine production by the TH1 subset, resulting in decreased levels of IL-2, TNF, and IFN-. Influenza Has Been Responsible for Some of the Worst Pandemics in History The influenza virus infects the upper respiratory tract and major central airways in humans, horses, birds, pigs, and even seals. In 1918–19, an influenza pandemic (worldwide epidemic) killed more than 20 million people, a toll surpass￾ing the number of casualties in World War I. Some areas, such as Alaska and the Pacific Islands, lost more than half of their population during that pandemic. PROPERTIES OF THE INFLUENZA VIRUS Influenza viral particles, or virions, are roughly spherical or ovoid in shape, with an average diameter of 90–100 nm. The virions are surrounded by an outer envelope—a lipid bilayer acquired from the plasma membrane of the infected host cell during the process of budding. Inserted into the envelope are two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which form radiating projections that are visible in electron micrographs (Figure 17-3). The hemagglutinin pro￾jections, in the form of trimers, are responsible for the attachment of the virus to host cells. There are approximately 1000 hemagglutinin projections per influenza virion. The hemagglutinin trimer binds to sialic acid groups on host-cell glycoproteins and glycolipids by way of a conserved amino acid sequence that forms a small groove in the hemagglu￾tinin molecule. Neuraminidase, as its name indicates, cleaves N-acetylneuraminic (sialic) acid from nascent viral glyco￾proteins and host-cell membrane glycoproteins, an activity that presumably facilitates viral budding from the infected host cell. Within the envelope, an inner layer of matrix pro￾tein surrounds the nucleocapsid, which consists of eight dif- 392 PART IV The Immune System in Health and Disease