Structural and Functional Constraints Limit Options for Cytotoxic T-Lymphocyte Escape in the Immunodominant HLA-B27-Restricted Epitope in Human Immunodeficiency Virus Type 1 Capsid
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Published:2008-06
Issue:11
Volume:82
Page:5594-5605
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ISSN:0022-538X
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Container-title:Journal of Virology
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language:en
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Short-container-title:J Virol
Author:
Schneidewind Arne1, Brockman Mark A.12, Sidney John3, Wang Yaoyu E.1, Chen Huabiao12, Suscovich Todd J.1, Li Bin1, Adam Rahma I.1, Allgaier Rachel L.1, Mothé Bianca R.4, Kuntzen Thomas1, Oniangue-Ndza Cesar1, Trocha Alicja1, Yu Xu G.1, Brander Christian1, Sette Alessandro3, Walker Bruce D.12, Allen Todd M.1
Affiliation:
1. Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 2. Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 3. La Jolla Institute for Allergy and Immunology, La Jolla, California 4. Department of Biological Sciences, California State University, San Marcos, California
Abstract
ABSTRACT
Control of human immunodeficiency virus type 1 (HIV-1) by HLA-B27-positive subjects has been linked to an immunodominant CD8
+
cytotoxic T-lymphocyte (CTL) response targeting the conserved KK10 epitope (KRWIILGLNK
263-272
) in p24/Gag. Viral escape in KK10 typically occurs through development of an R
264
K substitution in conjunction with the upstream compensatory mutation S
173
A, and the difficulty of the virus to escape from the immune response against the KK10 epitope until late in infection has been associated with slower clinical progression. Rare alternative escape mutations at R
264
have been observed, but factors dictating the preferential selection of R
264
K remain unclear. Here we illustrate that while all observed R
264
mutations (K, G, Q, and T) reduced peptide binding to HLA-B27 and impaired viral replication, the replicative defects of the alternative mutants were actually less pronounced than those for R
264
K. Importantly, however, none of these mutants replicated as well as an R
264
K variant containing the compensatory mutation S
173
A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R
264
K mutant also displayed the highest replication capacity in the presence of KK10-specific CTLs. Comparisons of codon usage for the respective variants indicated that generation of the R
264
K mutation may also be favored due to a G-to-A bias in nucleotide substitutions during HIV-1 replication. Together, these data suggest that the preference for R
264
K is due primarily to the ability of the S
173
A-compensated virus to replicate better than alternative variants in the presence of CTLs, suggesting that viral fitness is a key contributor for the selection of immune escape variants.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
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