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Chapter 22 : Immunology and AIDS

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Abstract:

This chapter discusses 1) the basics of acquired immunodeficiency syndrome (AIDS), 2) the structure, function, and biology of human immunodeficiency virus (HIV), 3) genetic and molecular characterization of the HIV genome, 4) pathogenesis of HIV infection and development of AIDS, 5) compromise to the immune system by HIV infection, 6) immune responses to HIV, 7) HIV evasion of immune responses, 8) drugs that are used to treat HIV infection, and 9) vaccines to prevent HIV infection and AIDS. HIV-1 contains the three major genes for structural proteins typical of retroviruses: , polymerase (), and envelope (). In general, these genes are translated into precursor proteins that then undergo cleavage and processing to form the mature subunit proteins used for virus assembly. Functionally, almost all aspects of immunity are affected as the disease progresses. There is a conspicuous loss of cellular immunity and an increased susceptibility to intracellular pathogens such as mycobacteria and viruses. In time, drugs that targeted HIV-1 itself were developed, the first being zidovudine (ZDV [AZT]). All the early agents were nucleoside analog inhibitors of viral reverse transcriptase. Most of the attempts at human HIV vaccines have been based on empirical approaches without the intent of generating a specific type of immune effector. Combination multidrug therapy has temporarily provided a solution to this problem, since the application of several antiviral drugs requires that a viral variant become simultaneously resistant to all of the component drugs.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22

Key Concept Ranking

Infection and Immunity
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Innate Immune System
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Human immunodeficiency virus 1
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MHC Class I
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Figures

Image of Figure 22.1
Figure 22.1

Structure of the HIV virion. The infectious particle contains duplicate strands of viral RNA genome in tight association with the viral proteins p7 and p9 . This RNA complex is packaged into a bullet-shaped capsid (composed of the viral protein p24) along with viral enzymes integrase (p32), protease (p10), and two copies of RT (p64). These enzymes play important roles in the viral infectious cycle. The viral capsid is further enclosed within an “outer core” composed of viral p17 protein. This entire particle is enclosed in a membrane envelope derived from the virus's most recent host cell. This envelope contains many host proteins (e.g., host's MHC class I) as well as the viral proteins gp41 and gp120 which are important for docking and entry of the virion with its host cell.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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Image of Figure 22.2
Figure 22.2

Infection of a host CD4 cell by HIV (see Fig. 22.1 for identification of structures). The initial interaction of the virion with its host cell is the binding of viral gp120 with host cell CD4 protein (). This induces a conformational shift in gp120 that exposes the chemokine-binding site (), which subsequently interacts () with the host cell's chemokine receptor CXCR4 (on CD4 T cells) or CCR5 (on monocytes). This second interaction triggers conformational shifts in gp41 that expose the fusigenic domain of gp41 (), initiating virion-host-cell fusion () and introducing the viral capsid into the host cell (). The viral capsid is dissembled, freeing the viral genome (). Viral RT then synthesizes a complementary DNA strand using the single- stranded viral genome RNA as a template (), and then degrades the original RNA strand, leaving a single-stranded DNA copy of the viral genome (). Host-cell enzymes then synthesize a complementary DNA strand, making the viral genome into double-stranded DNA (), which enters the nucleus with the help of the viral Vpr protein and inserts into the host cell's DNA via the action of viral integrase enzyme (). Diagrams of the HIV receptor, CD4 (), and coreceptors, the chemokine receptors CCR5 and CXCR4 () on T lymphocytes. () Diagram of the CD4 glycoprotein. HIV binds to the D1 and D2 domains, which form a rigid unit. The crystal structure of the D1 and D2 chemokine receptor family is at the right. () Diagram of the chemokine receptor family of receptors, showing bound ligand (red). The cylinders represent transmembrane-spanning regions, of which there are seven. Reprinted from J. H. Wang, 10799–10804, 2001 , and L. O. Gerlach et al., 14153–14160, 2001 , with permission.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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Image of Figure 22.3
Figure 22.3

HIV activation and replication. Integrated prophage is transcribed by host RNAP II () from promoters located in the virus's LTRs ( Fig. 22.4 ). These viral transcripts either are exported from the nucleus to be assembled into new phage particles () or are translated into viral proteins in the cytoplasm (). Some viral proteins are synthesized as mature proteins that will be assembled into nascent viral capsids (), others such as the gp41-gp120 complex are transported to the host cell membrane (), and still others are translated as precursor proteins that require proteolytic cleavage to be converted to their mature form (). On the host cell surface, some gp120 protein can spontaneously dissociate from gp41 (); this soluble gp120 protein has been implicated in some aspects of HIV pathogenesis. Assembly of new viral particles proceeds as single-stranded viral RNA is complexed with viral p7 and p9 proteins () and is then packaged into a capsid composed of viral p24 and p17 proteins (). Nascent viruses either can bud from the host cell membrane to produce new, infectious virions () or, alternatively, can bind directly to CD4 receptors of neighboring host cells before budding occurs (). In the latter case, virus can be spread from one infected host cell directly to another host cell without generating a virion intermediate (). In the diagram, the second host cell is depicted in pink (rather than yellow) for clarity, although the two host cells may, in fact, be the same type of cell.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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Image of Figure 22.4
Figure 22.4

Organization of HIV genetic coding regions. The HIV genome is approximately 10 kilobases long and contains genes for nine primary translation products. The coding regions of , and overlap reading frames of other HIV genes. The and genes have two exons that must be joined by splicing before translation. The primary translation products for the , and genes are precursors that must be proteolytically processed to generate mature viral proteins.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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Image of Figure 22.5
Figure 22.5

Regulation of transcription of HIV mRNA. Transcription proceeds normally until RNA polymerase (Pol) II crosses the region of HIV containing the TAR sequence. TAR RNA forms a large hairpin-loop secondary structure that stalls further transcription. Binding of the Tat and CycT proteins to the TAR loop structure helps recruit CDK-9, which phosphorylates the RNA polymerase. This phosphorylation event relieves transcription repression, allowing transcription to proceed.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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Image of Figure 22.6
Figure 22.6

Immunopathogenesis of HIV infection. The pathogenesis of HIV has two stages. The early stage of infection takes place within the first several weeks of infection and presents as a flu-like syndrome (which is usually not recognized as HIV infection). This is a viremic state marked by a temporary decrease in the number of circulating CD4T cells. After several weeks, the viral load is controlled by the host's immune response, and the number of CD4 T cells slowly recovers to almost normal levels. This marks the beginning of an asymptomatic latent period, which usually lasts up to about 10 years. Later in this asymptomatic period, the number of CD4 T cells begins to decline gradually. Eventually, the CD4 cell count becomes low enough to compromise host immunity. The viral load rapidly escalates at this time, and the host also may begin to experience opportunistic infection by other bacterial, viral, and fungal pathogens.

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
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References

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1. Blankson, J. N.,, J. E. Gallant,, and R. F. Siliciano. 2001. Proliferative responses to human immunodeficiency virus type 1 (HIV- 1) antigens in HIV-1-infected patients with immune reconstitution. J. Infect. Dis. 183:657661.
2. Center, D. M.,, H. Kornfeld,, T. C. Ryan,, and W. W. Cruikshank. 2000. Interleukin 16: implications for CD4 functions and HIV progression. Immunol. Today 21:273280.
3. Chinen, J.,, and W.T. Shearer. 2002. Molecular virology and immunology of HIV infection. J. Allergy Clin. Immunol. 110:189198.
4. Garnett, G. P.,, L. Bartley,, N. C. Grassly,, and R. M. Anderson. 2002. Antiretroviral therapy to treat and prevent HIV/AIDS in resource-poor settings. Nat. Med. 8:651654.
5. Greene, W. C.,, and B. M. Peterlin. 2002. Charting HIV’s remarkable voyage through the cell: basic science as a passport to future therapy. Nat. Med. 8:673680.
6. Ho, D. D.,, and Y. Huang. 2002. The HIV-1 vaccine race. Cell 110:135138.
7. Mascola, J. R.,, and G. J. Nabel. 2001. Vaccines for the prevention of HIV-1 disease. Curr. Opin. Immunol. 13:489495.
8. Moylett, E. H.,, and W. T. Shearer. 2002. HIV: clinical manifestations. J. Allergy Clin. Immunol. 110:316.
9. Piguet, V.,, and D. Trono. 2001. Living in oblivion: HIV immune evasion. Semin. Immunol. 13:5157.
10. Turville, S. G.,, P. U. Cameron,, A. Handley,, G. Lin,, S. Pohlmann,, R. W. Doms,, and A. L. Cunningham. 2002. Diversity of receptors binding HIV on dendritic cell subsets. Nat. Immunol. 3:975983.
11. Yoshizawa, I.,, Y. Soda,, T. Mizuochi,, S. Yasuda,, T. A. Rizvi,, T. Takemori,, and Y. Tsunetsugu-Yokota. 2001. Enhancement of mucosal immune response against HIV-1 Gag by DNA immunization. Vaccine 19:29953003.

Tables

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Table 22.1

Mechanisms of leukopenia caused by chronic HIV-1 infection

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
Generic image for table
Table 22.2

Secreted factors that inhibit HIV-1 infection

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22
Generic image for table
Table 22.3

Mechanisms by which HIV-1 evades host immunity

Citation: Boisot S, Pier G. 2004. Immunology and AIDS, p 531-552. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch22

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