Chapter 33 : Human Immunodeficiency Virus

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The current designations of specific human immunodeficiency virus (HIV)-1 strains as circulating recombinant form (CRF) versus parental subtypes are subject to change, since putative evolutionary relationships can be confounded by sampling history and high rates of recombination. Disorders of the peripheral nervous system can be classified as distal symmetric polyneuropathy, toxic neuropathy, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, and mononeuropathy multiplex. The major causes of transmission of HIV, sexual intercourse and injection drug use, represent two extremely strong biological drives. The ultimate goal of chemotherapy of HIV is to thus identify drug regimens that completely inhibit virus replication. Although any function in a genetically efficient organism is a candidate for an inhibitory drug, the currently approved drugs are directed against reverse transcriptase (RT), protease (PR), integrase (IN), and viral entry, with the RT inhibitors being classified as nucleosides or nonnucleosides. The correlation of risk of progression with certain class I human leukocyte antigen (HLA) haplotypes and with the breadth and magnitude of cell-mediated immune responses has prompted interest in therapeutic immunization to enhance these beneficial responses. This approach in general has been aimed at delivering immunogens while the immune system is fully protected by potent antiretroviral chemotherapy and then ascertaining whether a benefit can be discerned after withdrawal of therapy.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 1

Evolutionary relationships between members of the HIV-1 and SIVcpz lineages, based on the phylogenetic analysis of Env protein sequences. The three genetic groups of HIV-1 (M, N, and O) are indicated by brackets on the right, as are related groups of SIVcpz strains from the apparent nonhuman primate source of HIV-1 strains. Five subtypes within group M are also indicated. The scale bar indicates 0.1 amino acid replacement per site. (Modified from reference with permission of the American Association for the Advancement of Science.)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 2

(A) Structural representation of the envelope glycoprotein complex of HIV-1 interacting with the cellular receptor molecules CD4 and CCR5. The shaded area at the top represents the viral lipid envelope; that at the bottom represents the cellular plasma membrane. The surface subunit gp120 and the transmembrane subunit gp41 of HIV Env form a trimeric complex. The variable loops of the gp120 are not shown and would extend over the outer surface of the complex. (B) Structural representation of the gp120 surface, emphasizing the relationships among the binding sites for CD4 and CCR5, the location of neutralization epitopes, and the protection from antibody responses afforded by the variable loops and by glycosylation. (Panel 1) Surface of the core of gp120, missing most of the major variable loops (V1, V2, V3, and V4). The arrow points to the viral membrane. The interaction sites for CCR5 are lightly shaded; those for CD4 are more darkly shaded. (Panel 2) Conserved neutralization epitopes are indicated: the CD4BS epitopes are darkly shaded, the CD4i epitopes are lightly shaded, and the 2G12 epitope is darkly shaded and toward the right; see the text for definition. (Panel 3) Protection from antibody responses is provided by the V2 and V3 loops, as well as by N-linked glycosylation (sites are shaded). (Panel 4) The neutralizing face of gp120 (light shading) includes the binding sites for CD4 and CCR5; the nonneutralizing face (dark shading) includes the region that interacts with gp41; and the silent face (white) is minimally immunogenic due to glycosylation. (Modified from reference with permission of the American Association for the Advancement of Science.)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 3

Electron micrograph of an HIV-1 virion budding from an infected cell. The viral glycoprotein complexes are barely discernible on the surface of the virion membrane. The electron-dense material just beneath the viral lipid bilayer corresponds to the MA (p17) protein. The conical virion core is composed of the CA (p24) protein. Also within the core are the NC (p7) protein which binds the genomic RNA, the p6 protein required for budding, the accessory protein Vpr, the RT, the IN, and two copies of the genomic RNA. The accessory protein Nef is also virion-associated. (Micrograph courtesy of H. Gelderbloom.)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 4

Genomic organization of HIV-1 and HIV-2. The viral open reading frames are shown; the roles of their gene products are described in the text and in Table 1 . The open reading frames of the and genes are interrupted by an intron. The LTRs found at each end of the fully reverse-transcribed viral DNA are composed of U3, R, and U5 regions; the definitions of their boundaries are described in the text. The major genetic differences between these viruses are the lack of the Vpu open reading frame and the presence of the Vpx open reading frame in HIV-2; these features render HIV-2 more similar to most SIVs than to HIV-1.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 5

Replication cycle of HIV.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 6

Formation of syncytia during replication of HIV-1 in a culture of T lymphoblastoid cells. In immortalized T-cell lines, the interaction of the viral glycoprotein complex with the cellular receptors CD4 and CXCR4 allows cell-cell fusion and the formation of multinucleated giant cells.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 7

Cellular dynamics of HIV-1 infection of CD4 T cells. Successive steps in the life cycle of the virus are indicated by horizontal arrows. Transitions between resting (small) and activated (large) CD4 T cells are illustrated by vertical arrows. HIV-1 can infect resting and activated CD4 T cells, but integration of the reverse-transcribed HIV-1 provirus, which is necessary for virus production, occurs only in antigen-activated T cells. Productive infection requires antigen (Ag)-driven activation of recently infected resting CD4 cells or infection of antigen-activated CD4 T cells. Productively infected cells generally die within a few days from cytopathic effects of the infection, but some survive long enough to go back to a resting state, thereby establishing a stable latent reservoir.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 8

The three stages of disease in a hypothetical case of HIV-1 infection. Solid line, CD4 count; broken line, plasma HIV RNA.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 9

Hypothetical plot of plasma virus in a patient who is taking an effective regimen of drugs that block infection of new cells. The plasma virus level drops rapidly in the first 2 weeks of treatment, reflecting the short half-life of the virus in plasma and the short half-life of most of the productively infected cells. These cells appear to be activated CD4 T cells. The decline in plasma virus level shows a second, slower phase, which is due to turnover of cells infected before initiation of therapy. These may be persistently infected macrophages or CD4 T cells that are in a lower state of activation. Alternatively, this RNA could represent the clearance of virions that had accumulated in the germinal centers of lymphoid tissue. The second phase brings the viral load down to below the limit of detection, but the virus persists in reservoirs, including an extremely stable reservoir of latent virus in resting memory CD4 T cells.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 10

(a) Estimated number of AIDS cases and deaths of adults and adolescents with AIDS in the United States and dependent areas during the period from 1985 to 2005. The number of deaths is adjusted for reporting delays. (b) Estimated proportion of persons surviving with AIDS in the United States and dependent areas by year of diagnosis. With new infections continuing unabated and with survival increasing as a result of improving treatment, one consequence is the progressive accumulaton of persons living with HIV infection. (Both figures adapted from the CDC [http://www.cdc.gov/hiv/].)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 11

Three-year treatment with indinavir, zidovudine, and lamivudine. (a) Median changes in serum HIV RNA level (Amplicor assay with quantification limit of 500 copies/ml) from baseline. (b) Proportions of patients with serum HIV RNA levels lower than 50 copies/ml (ultradirect assay). (c) Median changes in CD4 cell count from baseline. The number of contributing patients in each trial and at each time point was between 30 and 33. Details regarding the study and analyses are published in reference . (Adapted from reference with permission.)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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Image of FIGURE 12

Hypothetical impact of antiviral drug activity on the probability of the emergence of drug resistance. (Reprinted from reference .)

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2009. Human Immunodeficiency Virus, p 737-783. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch33
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