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Chapter 9 : Host-Driven Plasticity of the Human Immunodeficiency Virus Genome

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Abstract:

This chapter describes the scale and driving force behind the profound genomic plasticity of human immunodeficiency virus (HIV). It discusses the intense interplay between the virus and the immune system of the host. It also speculates on the impact of this variability on the prospects for the development of effective vaccines and novel therapies. The evolution of HIV is, as with all organisms, driven predominantly by Darwinian natural selection that comprises two fully independent but essential components. The first is the production of random mutations that form a pool of organisms differing slightly in pheno-type. Second, is selective pressure that drives the rapid and spectacular evolution of HIV. Neutralizing antibodies produced are relatively type specific and targeted to one or two regions of the envelope glycoprotein that are relatively free to mutate without the virus taking a significant fitness hit. The options open to the virus for escaping cytotoxic T lymphocyte (CTL) recognition are numerous. First, it may alter one of the amino acids in the epitope necessary for recognition by the corresponding CTL T-cell receptor. In addition to the extreme selection pressure exerted on HIV by the immune system, there is an additional "artificial" pressure driving HIV evolution, particularly in industrialized countries.

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9

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Image of FIGURE 1
FIGURE 1

Mechanisms of genomic variation. Three main mechanisms contribute to the extensive genomic variation within the HIV genome. (A) In the absence of a proofreading function, transcription errors made by the viral reverse transcriptase enzyme during the synthesis of a DNA copy of the RNA genome result in (nearly) random mutations that accumulate if beneficial. (B) Template switching of reverse transcriptase from one RNA template to another. Distinct mutations in regions either side of the switching event can then become incorporated into a single genome. (C) Template switching between distinct viral subtypes. In the rare cases of simultaneous infection with two viral subtypes, switching can occur yielding a radically new virus with a mosaic genome. Adapted from .

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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Image of FIGURE 2
FIGURE 2

Phylogenetic relationships between strains of SIV infecting diverse species of African primates. Shown is the degree of heterogeneity within a portion of the gene, with the bar representing 0.1 replacement per site. Adapted from . doi:10.1128/9781555817213.ch09f02

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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Image of FIGURE 3
FIGURE 3

Mosaic genome of SIVcpz (and therefore HIV-1). Sequence analyses reveal that the LTRs and the , and genes are derived from the SIVrcm lineage whereas the gene and the 3′ exons of and originate from the SIVgsn/mus/mon lineage. The origin of the 5′ exons of and is unclear. Adapted from . doi:10.1128/9781555817213.ch09f03

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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Image of FIGURE 4
FIGURE 4

Comparison of genomic variability. The degree of variation within the HIV envelope glycoprotein in a long-term singly infected individual is comparable to the global variation of the influenza A H3 hemagglutinin protein in 1 year. Variation of the envelope gene within one African nation (Democratic Republic of Congo) is dramatically higher. Adapted from . doi:10.1128/9781555817213.ch09f04

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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Image of FIGURE 5
FIGURE 5

Rapid and extensive variation within a CTL epitope. Ultradeep pyrosequencing of the SIVmac gene after infection of cynomolgus macaques reveals the appearance of variants within only 17 days. Such variants, particularly those with mutations within the RM9 CTL epitope, come to dominate the viral population during the ensuing weeks. Adapted from . doi:10.1128/9781555817213.ch09f05

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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Image of FIGURE 6
FIGURE 6

Escape from virus-specific CTL recognition. A CTL epitope (blue) within a viral protein is normally processed, bound to an MHC-I molecule, and presented via the endoplasmic reticulum (ER)/Golgi complex on the surface of the cell to be recognized by the corresponding T-cell receptor (TCR) expressed by a CTL. Mutations resulting in the substitution (red) of an amino acid normally recognized by the TCR may result in suboptimal or even no recognition. Mutations resulting in changes of an “anchor” residue can inhibit formation of the MHC-I/β2-microglobulin/epitope complex, preventing expression at the cell surface. Finally, changes in amino acids flanking the epitope may prevent even the wild-type sequence from being processed and expressed. Adapted from . doi:10.1128/9781555817213.ch09f06

Citation: Norley S, Kurth R. 2012. Host-Driven Plasticity of the Human Immunodeficiency Virus Genome, p 143-161. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch9
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