This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. E. Articles by Allen, T. M. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. E. Articles by Allen, T. M.

 Previous Article  |  Next Article 

Journal of Virology, February 2009, p. 1845-1855, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01061-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Protective HLA Class I Alleles That Restrict Acute-Phase CD8⁺ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1 ^,

Yaoyu E. Wang,^1, Bin Li,^1, Jonathan M. Carlson,² Hendrik Streeck,¹ Adrianne D. Gladden,¹ Robert Goodman,¹ Arne Schneidewind,¹ Karen A. Power,¹ Ildiko Toth,¹ Nicole Frahm,¹ Galit Alter,¹ Christian Brander,^1,¶ Mary Carrington,³ Bruce D. Walker,^1,4 Marcus Altfeld,¹ David Heckerman,² and Todd M. Allen^1*

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts,¹ Microsoft Research, Redmond, Washington,² Laboratory of Genomic Diversity, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland,³ Howard Hughes Medical Institute, Chevy Chase, Maryland⁴

Received 20 May 2008/ Accepted 11 November 2008

The control of human immunodeficiency virus type 1 (HIV-1) associated with particular HLA class I alleles suggests that some CD8⁺ T-cell responses may be more effective than others at containing HIV-1. Unfortunately, substantial diversities in the breadth, magnitude, and function of these responses have impaired our ability to identify responses most critical to this control. It has been proposed that CD8 responses targeting conserved regions of the virus may be particularly effective, since the development of cytotoxic T-lymphocyte (CTL) escape mutations in these regions may significantly impair viral replication. To address this hypothesis at the population level, we derived near-full-length viral genomes from 98 chronically infected individuals and identified a total of 76 HLA class I-associated mutations across the genome, reflective of CD8 responses capable of selecting for sequence evolution. The majority of HLA-associated mutations were found in p24 Gag, Pol, and Nef. Reversion of HLA-associated mutations in the absence of the selecting HLA allele was also commonly observed, suggesting an impact of most CTL escape mutations on viral replication. Although no correlations were observed between the number or location of HLA-associated mutations and protective HLA alleles, limiting the analysis to mutations selected by acute-phase immunodominant responses revealed a strong positive correlation between mutations at conserved residues and protective HLA alleles. These data suggest that control of HIV-1 may be associated with acute-phase CD8 responses capable of selecting for viral escape mutations in highly conserved regions of the virus, supporting the inclusion of these regions in the design of an effective vaccine.

---

* 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

Published ahead of print on 26 November 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

Y.E.W. and B.L. contributed equally to this study.

^¶ Present address: Laboratori de Retrovirologia, Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, 08916 Badalona, Barcelona, Catalonia, Spain.

---

Journal of Virology, February 2009, p. 1845-1855, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01061-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Korber, B. T., Letvin, N. L., Haynes, B. F. (2009). T-Cell Vaccine Strategies for Human Immunodeficiency Virus, the Virus with a Thousand Faces. J. Virol. 83: 8300-8314 [Full Text]