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Journal of Virology, June 2008, p. 5594-5605, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02356-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Arne Schneidewind,1,{dagger} Mark A. Brockman,1,2,{dagger} John Sidney,3 Yaoyu E. Wang,1 Huabiao Chen,1,2 Todd J. Suscovich,1 Bin Li,1 Rahma I. Adam,1 Rachel L. Allgaier,1 Bianca R. Mothé,4 Thomas Kuntzen,1 Cesar Oniangue-Ndza,1 Alicja Trocha,1 Xu G. Yu,1 Christian Brander,1 Alessandro Sette,3 Bruce D. Walker,1,2 and Todd M. Allen1*

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,1 Howard Hughes Medical Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,2 La Jolla Institute for Allergy and Immunology, La Jolla, California,3 Department of Biological Sciences, California State University, San Marcos, California4

Received 31 October 2007/ Accepted 17 March 2008

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 (KRWIILGLNK263-272) in p24/Gag. Viral escape in KK10 typically occurs through development of an R264K substitution in conjunction with the upstream compensatory mutation S173A, 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 R264 have been observed, but factors dictating the preferential selection of R264K remain unclear. Here we illustrate that while all observed R264 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 R264K. Importantly, however, none of these mutants replicated as well as an R264K variant containing the compensatory mutation S173A. In assessing the combined effects of viral replication and CTL escape using an in vitro coculture assay, we further observed that the compensated R264K 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 R264K 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 R264K is due primarily to the ability of the S173A-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.

* Corresponding author. Mailing address: MGH-East, CNY 6625, 149 13th Street, Charlestown, MA 02129. Phone: (617) 726-7846. Fax: (617) 724-8586. E-mail: tallen2{at}partners.org

{triangledown} Published ahead of print on 2 April 2008.

{dagger} Both authors contributed equally.

Journal of Virology, June 2008, p. 5594-5605, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02356-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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