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Chapter 34 : Human Immunodeficiency Virus

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Human Immunodeficiency Virus, Page 1 of 2

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Abstract:

Infection with human immunodeficiency virus type 1 (HIV-1) is prevalent throughout the world and is characterized by a progressive deterioration of the immune system that is usually fatal if untreated. As of 2013, HIV-1 was estimated to infect 35 million people worldwide (http://www.who.int/hiv/data/en/). Over 95% of these infections are in low- and middle-income countries among young adults. The acquired immunodeficiency syndrome (AIDS) that results from chronic HIV-1 infection is the sixth leading cause of mortality worldwide; it was estimated to have caused 1.5 million deaths in 2013 (http://www.who.int/hiv/data/en/).

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 1
FIGURE 1

The genetic relatedness of different HIV and simian immunodeficiency virus (SIV) strains. 87 human and simian lentiviruses were compared by aligning their full-genome sequences. Phylogenetic trees based on nucleotide distance were constructed by neighbor-joining methods. HIV-2 and HIV-1 share only 50 to 60% sequence identity and cluster at distinct locations on the phylogenetic tree, whereas SIV branches out from the root of the HIV-1 groups. The origins of these HIV-1 groups in southern Cameroon indicate two probable jumps from chimpanzee (groups M and N) and gorilla (group O) species. HIV-1 M subtypes probably evolved from a discrete introduction into the human population and then diverged into different subtypes. The subtypes defined as “A-like” describe HIV-1 isolates with sequences that map phylogenetically more to subtype A than to any other subtype. For example, the recombinant form CRF02_AG (such as 02 AG.NG.IBNG in the HIV-1 group M A-like cluster) has longer genomic segments that are more related to subtype A than to subtype G. M, main; N, new. (Modified with permission from [ ]).

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 2
FIGURE 2

Structure and antibody recognition of the HIV envelope spike. The molecule is a heterotrimer of composition (gp120)3 (gp41)3. Gp41 is a transmembrane protein and gp120 is the receptor molecule for CD4 and CCR5 (or CXCR4). The model is adapted from a cryo-electron tomographic structure of the HIV trimer, with the crystal structure of the b12-antibody-bound monomeric gp120 core (red) fitted into the electron density map. Glycans are shown in purple. The CD4 binding site is shown in yellow. The approximate locations of the epitopes targeted by existing broadly-neutralizing monoclonal antibodies (bnMAbs) are indicated with arrows, and the number of MAbs targeting each epitope is shown in red boxes. A small selection of bnMAbs targeting each epitope is included. Modified with permission from [ ]).

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 3
FIGURE 3

Electron micrograph of an HIV-1 virion budding from an infected cell. The viral glycoprotein complexes are barely discernable 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 with the core are the NC (p7) protein, which binds the genomic RNA, the p6 protein required for budding, the accessory protein Vpr, the reverse transcriptase, the integrase, 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. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 4
FIGURE 4

Genomic organization of HIV-1 and HIV-2. The viral open reading frames (ORFs) are shown; the roles of their gene products are described in the text and in Table 1 . The ORFs of the and genes are interrupted by an intron. The long terminal repeats (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 ORF and the presence of the Vpx ORF 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. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 5
FIGURE 5

Replication cycle of HIV.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 6
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. The formation of syncytia begins with cell clustering, followed by cell-cell fusion and the ballooning of cell membranes.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 7
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-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. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 8
FIGURE 8

The three stages of disease in a hypothetical case of HIV-1 infection.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 9
FIGURE 9

Hypothetical plot of plasma virus in a patient who is started on an effective regimen of drugs that block infection of new cells. Plasma virus titer drops rapidly in the first two weeks of treatment, reflecting the short plasma half-life of the virus 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 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. Reproduced from reference ( ) with permission.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 10
FIGURE 10

Order of appearance of laboratory markers of HIV-1 infection ( ).

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 11
FIGURE 11

Testing algorithm for HIV diagnosis ( ).

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 12
FIGURE 12

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

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 13
FIGURE 13

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

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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Image of FIGURE 14
FIGURE 14

Hypothetical impact of antiviral drug activity upon the probability of the emergence of drug resistance. From reference ( ) with permission.

Citation: Guatelli J, Siliciano R, Kuritzkes D, Richman D. 2017. Human Immunodeficiency Virus, p 795-840. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch34
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