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Pathogenesis and Immunity

Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters

Jaclyn K. Wright, Zabrina L. Brumme, Jonathan M. Carlson, David Heckerman, Carl M. Kadie, Chanson J. Brumme, Bingxia Wang, Elena Losina, Toshiyuki Miura, Fundisiwe Chonco, Mary van der Stok, Zenele Mncube, Karen Bishop, Philip J. R. Goulder, Bruce D. Walker, Mark A. Brockman, Thumbi Ndung'u
Jaclyn K. Wright
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Zabrina L. Brumme
2Simon Fraser University, Burnaby, Canada
3BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Jonathan M. Carlson
4eScience Group, Microsoft Research, Redmond, Washington
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David Heckerman
4eScience Group, Microsoft Research, Redmond, Washington
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Carl M. Kadie
4eScience Group, Microsoft Research, Redmond, Washington
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Chanson J. Brumme
3BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Bingxia Wang
5Program in HIV Outcomes Research, Massachusetts General Hospital, Boston, Massachusetts
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Elena Losina
5Program in HIV Outcomes Research, Massachusetts General Hospital, Boston, Massachusetts
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Toshiyuki Miura
6Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Fundisiwe Chonco
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Mary van der Stok
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Zenele Mncube
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Karen Bishop
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Philip J. R. Goulder
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
7Department of Paediatrics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
8Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts
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Bruce D. Walker
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
8Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts
9Howard Hughes Medical Institute, Chevy Chase, Maryland
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Mark A. Brockman
2Simon Fraser University, Burnaby, Canada
3BC Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Thumbi Ndung'u
1HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
8Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts
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  • For correspondence: ndungu@ukzn.ac.za
DOI: 10.1128/JVI.01084-10
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ABSTRACT

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
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Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters
Jaclyn K. Wright, Zabrina L. Brumme, Jonathan M. Carlson, David Heckerman, Carl M. Kadie, Chanson J. Brumme, Bingxia Wang, Elena Losina, Toshiyuki Miura, Fundisiwe Chonco, Mary van der Stok, Zenele Mncube, Karen Bishop, Philip J. R. Goulder, Bruce D. Walker, Mark A. Brockman, Thumbi Ndung'u
Journal of Virology Sep 2010, 84 (20) 10820-10831; DOI: 10.1128/JVI.01084-10

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Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters
Jaclyn K. Wright, Zabrina L. Brumme, Jonathan M. Carlson, David Heckerman, Carl M. Kadie, Chanson J. Brumme, Bingxia Wang, Elena Losina, Toshiyuki Miura, Fundisiwe Chonco, Mary van der Stok, Zenele Mncube, Karen Bishop, Philip J. R. Goulder, Bruce D. Walker, Mark A. Brockman, Thumbi Ndung'u
Journal of Virology Sep 2010, 84 (20) 10820-10831; DOI: 10.1128/JVI.01084-10
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KEYWORDS

HIV Infections
HIV-1
HLA Antigens
gag Gene Products, Human Immunodeficiency Virus

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