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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Progression to AIDS in south africa is associated with both reverting and compensatory viral mutations
PLoS ONE, Volume 6, No. 4, Article e19018, Year 2011
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Description
We lack the understanding of why HIV-infected individuals in South Africa progress to AIDS. We hypothesised that in end-stage disease there is a shifting dynamic between T cell imposed immunity and viral immune escape, which, through both compensatory and reverting viral mutations, results in increased viral fitness, elevated plasma viral loads and disease progression. We explored how T cell responses, viral adaptation and viral fitness inter-relate in South African cohorts recruited from Bloemfontein, the Free State (n = 278) and Durban, KwaZulu-Natal (n = 775). Immune responses were measured by γ-interferon ELISPOT assays. HLA-associated viral polymorphisms were determined using phylogenetically corrected techniques, and viral replication capacity (VRC) was measured by comparing the growth rate of gag-protease recombinant viruses against recombinant NL4-3 viruses. We report that in advanced disease (CD4 counts <100 cells/μl), T cell responses narrow, with a relative decline in Gag-directed responses (p<0.0001). This is associated with preserved selection pressure at specific viral amino acids (e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10 epitope), but with reversion at other sites (e.g., the T186S polymorphism within the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive of "immune relaxation". The median VRC from patients with CD4 counts <100 cells/μl was higher than from patients with CD4 counts ≥500 cells/μl (91.15% versus 85.19%, p = 0.0004), potentially explaining the rise in viral load associated with disease progression. Mutations at HIV Gag T186S and T242N reduced VRC, however, in advanced disease only the T242N mutants demonstrated increasing VRC, and were associated with compensatory mutations (p = 0.013). These data provide novel insights into the mechanisms of HIV disease progression in South Africa. Restoration of fitness correlates with loss of viral control in late disease, with evidence for both preserved and relaxed selection pressure across the HIV genome. Interventions that maintain viral fitness costs could potentially slow progression. © 2011 Huang et al.
Authors & Co-Authors
Huang, Kuan Hsiang Gary
United Kingdom, Oxford
Nuffield Department of Medicine
United Kingdom, Oxford
Oxford Social Sciences Division
Goedhals, Dominique
South Africa, Bloemfontein
University of the Free State
South Africa, Johannesburg
National Health Laboratory Service
Carlson, Jonathan M.
United States, Redmond
Microsoft Research
Brockman, Mark A.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
United States, Cambridge
Massachusetts Institute of Technology
Mishra, Swati
United Kingdom, Oxford
Nuffield Department of Medicine
Brumme, Zabrina L.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
United States, Cambridge
Massachusetts Institute of Technology
Hickling, Stephen
United Kingdom, Oxford
Nuffield Department of Medicine
Tang, Christopher S.W.
United Kingdom, Oxford
Nuffield Department of Medicine
Miura, Toshiyuki
United States, Cambridge
Massachusetts Institute of Technology
Japan, Tokyo
The University of Tokyo
Seebregts, Christopher John
South Africa, Tygerberg
South African Medical Research Council
Heckerman, David E.
United States, Redmond
Microsoft Research
Ndung'u, Thumbi P.
South Africa, Durban
University of Kwazulu-natal
Walker, Bruce D.
South Africa, Durban
University of Kwazulu-natal
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Harvard University
Klenerman, Paul
United Kingdom, Oxford
Nuffield Department of Medicine
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Steyn, Dewald
South Africa, Bloemfontein
University of the Free State
Goulder, Philip Jeremy Renshaw
United Kingdom, Oxford
University of Oxford
Phillips, Rodney E.
United Kingdom, Oxford
Nuffield Department of Medicine
United Kingdom, Oxford
Oxford Social Sciences Division
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
van Vuuren, Cloete
South Africa, Bloemfontein
University of the Free State
Frater, John
United Kingdom, Oxford
Nuffield Department of Medicine
United Kingdom, Oxford
Nihr Oxford Biomedical Research Centre
Statistics
Citations: 71
Authors: 19
Affiliations: 15
Identifiers
Doi:
10.1371/journal.pone.0019018
e-ISSN:
19326203
Research Areas
Infectious Diseases
Study Design
Cohort Study
Study Locations
South Africa