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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
Gag-protease-mediated replication capacity in HIV-1 subtype C chronic infection: Associations with HLA type and clinical parameters
Journal of Virology, Volume 84, No. 20, Year 2010
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Description
The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B*81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B*81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B*81, significantly influence Gag-protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression. Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC2950592/bin/supp_84_20_10820__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC2950592/bin/supp_84_20_10820__30junefiga1_paup.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC2950592/bin/supp_84_20_10820__Table_a1_16april.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC2950592/bin/supp_84_20_10820__Fig_A1_legend.doc
Authors & Co-Authors
Wright, Jaclyn K.
South Africa, Durban
The Nelson R. Mandela Medical School
Brumme, Zabrina L.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Carlson, Jonathan M.
United States, Redmond
Microsoft Research
Heckerman, David E.
United States, Redmond
Microsoft Research
Kadie, Carl M.
United States, Redmond
Microsoft Research
Brumme, Chanson J.
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Wang, Bingxia
United States, Boston
Massachusetts General Hospital
Losina, Elena
United States, Boston
Massachusetts General Hospital
Miura, Toshiyuki
Japan, Tokyo
The University of Tokyo
Chonco, Fundisiwe M.
South Africa, Durban
The Nelson R. Mandela Medical School
van der Stok, Mary
South Africa, Durban
The Nelson R. Mandela Medical School
Mncube, Zenele
South Africa, Durban
The Nelson R. Mandela Medical School
Bishop, Karen S.
South Africa, Durban
The Nelson R. Mandela Medical School
Goulder, Philip Jeremy Renshaw
South Africa, Durban
The Nelson R. Mandela Medical School
United Kingdom, Oxford
Nuffield Department of Medicine
United States, Cambridge
Harvard University
Walker, Bruce D.
South Africa, Durban
The Nelson R. Mandela Medical School
United States, Cambridge
Harvard University
United States, Chevy Chase
Howard Hughes Medical Institute
Brockman, Mark A.
Canada, Burnaby
Simon Fraser University
Canada, Vancouver
British Columbia Centre for Excellence in Hiv-aids
Ndung'u, Thumbi P.
South Africa, Durban
The Nelson R. Mandela Medical School
United States, Cambridge
Harvard University
Statistics
Citations: 102
Authors: 17
Affiliations: 9
Identifiers
Doi:
10.1128/JVI.01084-10
ISSN:
0022538X
e-ISSN:
10985514
Research Areas
Cancer
Health System And Policy
Infectious Diseases
Study Design
Cross Sectional Study
Cohort Study