Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C.

TitleInfluence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C.
Publication TypeJournal Article
Year of Publication2011
AuthorsWright JK, Novitsky V, Brockman MA, Brumme ZL, Brumme CJ, Carlson JM, Heckerman D, Wang B, Losina E, Leshwedi M, van der Stok M, Maphumulo L, Mkhwanazi N, Chonco F, Goulder PJR, Essex M, Walker BD, Ndung'u T
JournalJ Virol
Volume85
Issue8
Pagination3996-4006
Date Published04/2011
ISSN1098-5514
KeywordsAdult, Disease Progression, Female, gag Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV Protease, HIV-1, Humans, Male, Molecular Sequence Data, Polymorphism, Genetic, RNA, Viral, Sequence Analysis, DNA, Viral Load, Virulence, Virus Replication
Abstract

HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus.

DOI10.1128/JVI.02520-10
Alternate JournalJ. Virol.
PubMed ID21289112
PubMed Central IDPMC3126116
Grant ListR01 AI046995 / AI / NIAID NIH HHS / United States
R01-AI057027 / AI / NIAID NIH HHS / United States
R01-AI067073 / AI / NIAID NIH HHS / United States
R37 AI067073 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
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