Immunotherapy for Infectious Diseases
Immunotherapy for Infectious Diseases Immunotherapy for Infectious Diseases
Immunopathogenesis of HIV Disease 153 Viral replication continues within lymphoid tissue during the years of clinical latency (6), and the CD4� T-cell count gradually falls. As the lymphoid architecture becomes disrupted and the host immune defenses become exhausted, the virus reemerges. The patient experiences constitutional symptoms when the CD4� T-cell count falls to about 300 cells/mL. Opportunistic infections, wasting disease, and rare cancers occur when the CD4� T-cell count drops below 200 cells/mL. If this pattern is not reversed by potent antiretroviral therapy, death typically follows within 2 years. Variant Disease Courses Although progression from time of HIV infection to end-stage disease typically takes 8–10 years in the absence of potent antiretroviral therapy, there are also cases of either very rapid or slow disease progression. This variation has sometimes been linked to the characteristics of the infecting virus but more often seems to be a function of host immune response. Rapid progressors have sometimes been infected with an overwhelmingly large burden of virus, for instance, in the case of transfusion with heavily contaminated blood products. Other cases of rapid progression have been associated with primary HIV infection with strains that usually only arise late in disease course and that are able to bind to the �-chemokine receptor CXCR4 and induce syncytium formation. Failure to mount a broad enough host immunologic defense is a risk factor for rapid progression (7). At the other end of the spectrum are those rare individuals who exhibit long-term non-progression, maintaining low levels of plasma viremia and elevated CD4� T-cell counts in the absence of antiretroviral therapy, despite 10 or more years of infection. In a few cases, this has been associated with infection with a virus strain defective in essential viral genes (8–10). More often, these individuals are found to have competent viruses, but also a more preserved immune response, particularly characterized by retention of HIV-specific T-helper lymphocyte activity. Relative resistance to HIV infection or disease progression has been associated with different HLA groups (11) and with expression of mutant cell surface receptors for HIV, particularly the �-chemokine receptors (12). Pediatric HIV infection is also characterized by variation in rate of disease progression, with rapid progression to AIDS occurring about onethird of the time in the absence of potent therapy. Biology and Life Cycle of the Virus HIV-1 is icosahedral in structure, with an inner (p18) and outer membrane, a protein core (p24) containing two strands of genomic RNA bound to reverse transcriptase, and glycoprotein spikes extending from the outer membrane. The glycoprotein spikes are the two major viral envelope proteins, gp120 and gp41. Most of the outer envelope consists of host cell-derived proteins, including major histocompatibility complex antigens, acquired as the virus particle buds from the cell. The genome of HIV-1 is similar to that of other retroviruses, with gag encoding virion core proteins, env encoding envelope glycoproteins, and pol encoding the reverse transcriptase and integrase enzymes. In addition, the HIV-1 genome contains the regulatory genes nef, rev, tat, vif, vpr, and vpu. Regulatory elements are located in the long terminal repeats that flank the other genes. HIV infection begins with the binding of the gp120 V1 region to the cellular CD4� molecule, found predominantly on T-helper lymphocytes and monocytes/macrophages. This then results in a conformational change that exposes the gp120 V3 loop. Second
154 Fox receptor binding by the V3 loop is the next key step, which confers infectious tropism depending on the host receptor that the virus is able to utilize. Early in HIV infection, the infecting strains are typically best able to bind to the receptor CCR5 and are macrophage-tropic (13–17). With disease progression, more pathogenic strains arise that are able to bind to CXCR4 (18). These strains are able to replicate in transformed T-cell lines that express CXCR4, but not CCR5, and they induce syncytium formation. Other chemokine receptors have also been identified that HIV strains are able to utilize. Resistance to HIV infection has been linked to production of high levels of the natural ligands for these receptors, competing for binding with HIV (19,20), and with mutations in the genes coding for the receptors, yielding a poor match for HIV binding (21–23). Following binding by gp120 to both primary and secondary receptors, gp41 binding leads to fusion of viral and host cell membranes, uncoating of the HIV genomic RNA and its associated proteins, and its entry into the cell. HIV reverse transcriptase then makes a double-stranded DNA copy of the viral RNA, which is transported to the nucleus and integrated into the host cell chromosome by the viral integrase enzyme. The relative infidelity of the reverse transcriptase enzyme to the RNA template leads to a high mutation rate. Transcription of the integrated provirus is dependent on host cell activation and DNA-dependent RNA-polymerase activity. Initially, double-spliced viral mRNA is produced, coding for viral proteins. Later, as a result of the action of the HIV rev gene product, single-spliced and full-length HIV genomic RNA is produced and transported to the cytoplasm, where it is encapsulated in viral proteins. The virion buds from the host cell membrane and then matures into an infectious virus particle after cleavage of immature viral proteins by HIV protease. Each step of this complex life cycle presents opportunities for intervention with antiviral agents. PATHOLOGIC MANIFESTATIONS Host Response HIV disease is characterized by immune activation, which becomes chronic owing to its failure to clear the infection. This eventually leads to exhaustion of immunologic resistance and vulnerability to opportunistic disease. The unremitting inflammatory immune response also results in tissue damage, contributing to wasting, renal disease, cardiac disease, dementia, and neuropathy. Proinflammatory cytokines have been shown to stimulate HIV replication; therefore this response, which is elicited by HIV antigens, contributes to persistence of infection (24). The viremia during acute HIV infection falls as HIV is sequestered in lymphoid tissue, largely bound to follicular dendritic cells (FDCs), and as cytotoxic lymphocyte (CTL) response to HIV arises. Both infected and uninfected T-lymphocytes are also sequestered in the lymphoid tissues, in response to cytokine signaling and adhesion molecule expression. A significant amount of neutralizing antibody to HIV is usually detectable in the peripheral blood weeks after the plasma viral burden has fallen, suggesting that cell-mediated immunity is the more important initial host immune response (25). Studies of the breadth of CTL receptor V-� repertoire demonstrated more rapid disease progression when the repertoire was most limited (26). In contrast to the fall in CD4� T-cell numbers and function, CD8� T-cells are increased in both number and
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Immunopathogenesis of HIV Disease 153<br />
Viral replication continues within lymphoid tissue during the years of clinical<br />
latency (6), and the CD4� T-cell count gradually falls. As the lymphoid architecture<br />
becomes disrupted and the host immune defenses become exhausted, the virus<br />
reemerges. The patient experiences constitutional symptoms when the CD4� T-cell<br />
count falls to about 300 cells/mL. Opportunistic infections, wasting disease, and rare<br />
cancers occur when the CD4� T-cell count drops below 200 cells/mL. If this pattern<br />
is not reversed by potent antiretroviral therapy, death typically follows within 2 years.<br />
Variant Disease Courses<br />
Although progression from time of HIV infection to end-stage disease typically takes<br />
8–10 years in the absence of potent antiretroviral therapy, there are also cases of either<br />
very rapid or slow disease progression. This variation has sometimes been linked to the<br />
characteristics of the infecting virus but more often seems to be a function of host immune<br />
response. Rapid progressors have sometimes been infected with an overwhelmingly large<br />
burden of virus, <strong>for</strong> instance, in the case of transfusion with heavily contaminated blood<br />
products. Other cases of rapid progression have been associated with primary HIV infection<br />
with strains that usually only arise late in disease course and that are able to bind to<br />
the �-chemokine receptor CXCR4 and induce syncytium <strong>for</strong>mation. Failure to mount a<br />
broad enough host immunologic defense is a risk factor <strong>for</strong> rapid progression (7).<br />
At the other end of the spectrum are those rare individuals who exhibit long-term<br />
non-progression, maintaining low levels of plasma viremia and elevated CD4� T-cell<br />
counts in the absence of antiretroviral therapy, despite 10 or more years of infection.<br />
In a few cases, this has been associated with infection with a virus strain defective in<br />
essential viral genes (8–10). More often, these individuals are found to have competent<br />
viruses, but also a more preserved immune response, particularly characterized by<br />
retention of HIV-specific T-helper lymphocyte activity. Relative resistance to HIV<br />
infection or disease progression has been associated with different HLA groups (11)<br />
and with expression of mutant cell surface receptors <strong>for</strong> HIV, particularly the<br />
�-chemokine receptors (12). Pediatric HIV infection is also characterized by variation<br />
in rate of disease progression, with rapid progression to AIDS occurring about onethird<br />
of the time in the absence of potent therapy.<br />
Biology and Life Cycle of the Virus<br />
HIV-1 is icosahedral in structure, with an inner (p18) and outer membrane, a protein<br />
core (p24) containing two strands of genomic RNA bound to reverse transcriptase, and<br />
glycoprotein spikes extending from the outer membrane. The glycoprotein spikes are the<br />
two major viral envelope proteins, gp120 and gp41. Most of the outer envelope consists<br />
of host cell-derived proteins, including major histocompatibility complex antigens,<br />
acquired as the virus particle buds from the cell. The genome of HIV-1 is similar to that<br />
of other retroviruses, with gag encoding virion core proteins, env encoding envelope<br />
glycoproteins, and pol encoding the reverse transcriptase and integrase enzymes. In<br />
addition, the HIV-1 genome contains the regulatory genes nef, rev, tat, vif, vpr, and vpu.<br />
Regulatory elements are located in the long terminal repeats that flank the other genes.<br />
HIV infection begins with the binding of the gp120 V1 region to the cellular CD4�<br />
molecule, found predominantly on T-helper lymphocytes and monocytes/macrophages.<br />
This then results in a con<strong>for</strong>mational change that exposes the gp120 V3 loop. Second