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HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression.

Chang CH, Kist NC, Chester TL, Sreenu VB, Herman M, Luo M, Lunn D, Bell J, Plummer FA, Ball TB, Katzourakis A, Iversen AK - Sci Rep (2015)

Bottom Line: We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs.Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377).Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.

No MeSH data available.


Related in: MedlinePlus

Generation of HIV-1 recombinants and recombinant analyses.a. Example of a person infected with two HIV-1 subtypes (subtypes X and Y). Infection with the second HIV subtype (superinfection) may occur at any time after infection by the first HIV subtype but is most likely to occur during the first 6 months of initial infection in women18192425. The two HIV subtypes may infect the same target cell30, which can result in the packaging of two different viral RNA genomes into the same virion (highlighted in an orange circle, XY). b,c. Examples of infection with the XY virion and of HIV-1 recombination and selection. HIV reverse transcriptase (orange dot in the virion, orange line in the diagram) switches templates between RNA genome X and RNA genome Y to generate a unique recombinant form of the DNA strand (the resulting virion is highlighted in a grey circle, URFxy). Because this recombinant carries the HIV Y escape-mutation version of a targeted CD8 epitope, it is more fit than HIV X, and because this particular sequence combination results in faster replication than HIV Y, it is more fit to replicate and spread in the host than any of the parent viruses. Therefore, URFxy eventually dominates the viral population.
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f1: Generation of HIV-1 recombinants and recombinant analyses.a. Example of a person infected with two HIV-1 subtypes (subtypes X and Y). Infection with the second HIV subtype (superinfection) may occur at any time after infection by the first HIV subtype but is most likely to occur during the first 6 months of initial infection in women18192425. The two HIV subtypes may infect the same target cell30, which can result in the packaging of two different viral RNA genomes into the same virion (highlighted in an orange circle, XY). b,c. Examples of infection with the XY virion and of HIV-1 recombination and selection. HIV reverse transcriptase (orange dot in the virion, orange line in the diagram) switches templates between RNA genome X and RNA genome Y to generate a unique recombinant form of the DNA strand (the resulting virion is highlighted in a grey circle, URFxy). Because this recombinant carries the HIV Y escape-mutation version of a targeted CD8 epitope, it is more fit than HIV X, and because this particular sequence combination results in faster replication than HIV Y, it is more fit to replicate and spread in the host than any of the parent viruses. Therefore, URFxy eventually dominates the viral population.

Mentions: Because several HIV-1 strains co-circulate at high frequencies in some countries, e.g., Kenya272829, high-risk patients in these regions are frequently infected by more than one subtype/sub-subtype or CRF. If a cell is superinfected by HIV-1 virions from different subtypes/sub-subtypes/CRFs30, two viral RNA genomes from different subtypes/sub-subtypes/CRFs can be packaged into the same virion in that cell (Fig. 1a). After this virion infects the next target cell, RT can generate an inter-subtype unique recombinant form (URF) of the HIV-1 subtypes/sub-subtypes/CRFs that can be readily identified (Fig. 1b)31.


HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression.

Chang CH, Kist NC, Chester TL, Sreenu VB, Herman M, Luo M, Lunn D, Bell J, Plummer FA, Ball TB, Katzourakis A, Iversen AK - Sci Rep (2015)

Generation of HIV-1 recombinants and recombinant analyses.a. Example of a person infected with two HIV-1 subtypes (subtypes X and Y). Infection with the second HIV subtype (superinfection) may occur at any time after infection by the first HIV subtype but is most likely to occur during the first 6 months of initial infection in women18192425. The two HIV subtypes may infect the same target cell30, which can result in the packaging of two different viral RNA genomes into the same virion (highlighted in an orange circle, XY). b,c. Examples of infection with the XY virion and of HIV-1 recombination and selection. HIV reverse transcriptase (orange dot in the virion, orange line in the diagram) switches templates between RNA genome X and RNA genome Y to generate a unique recombinant form of the DNA strand (the resulting virion is highlighted in a grey circle, URFxy). Because this recombinant carries the HIV Y escape-mutation version of a targeted CD8 epitope, it is more fit than HIV X, and because this particular sequence combination results in faster replication than HIV Y, it is more fit to replicate and spread in the host than any of the parent viruses. Therefore, URFxy eventually dominates the viral population.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4469978&req=5

f1: Generation of HIV-1 recombinants and recombinant analyses.a. Example of a person infected with two HIV-1 subtypes (subtypes X and Y). Infection with the second HIV subtype (superinfection) may occur at any time after infection by the first HIV subtype but is most likely to occur during the first 6 months of initial infection in women18192425. The two HIV subtypes may infect the same target cell30, which can result in the packaging of two different viral RNA genomes into the same virion (highlighted in an orange circle, XY). b,c. Examples of infection with the XY virion and of HIV-1 recombination and selection. HIV reverse transcriptase (orange dot in the virion, orange line in the diagram) switches templates between RNA genome X and RNA genome Y to generate a unique recombinant form of the DNA strand (the resulting virion is highlighted in a grey circle, URFxy). Because this recombinant carries the HIV Y escape-mutation version of a targeted CD8 epitope, it is more fit than HIV X, and because this particular sequence combination results in faster replication than HIV Y, it is more fit to replicate and spread in the host than any of the parent viruses. Therefore, URFxy eventually dominates the viral population.
Mentions: Because several HIV-1 strains co-circulate at high frequencies in some countries, e.g., Kenya272829, high-risk patients in these regions are frequently infected by more than one subtype/sub-subtype or CRF. If a cell is superinfected by HIV-1 virions from different subtypes/sub-subtypes/CRFs30, two viral RNA genomes from different subtypes/sub-subtypes/CRFs can be packaged into the same virion in that cell (Fig. 1a). After this virion infects the next target cell, RT can generate an inter-subtype unique recombinant form (URF) of the HIV-1 subtypes/sub-subtypes/CRFs that can be readily identified (Fig. 1b)31.

Bottom Line: We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs.Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377).Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression.

No MeSH data available.


Related in: MedlinePlus