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Journal of Virology, September 2008, p. 9216-9227, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01041-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection {triangledown}

Zabrina L. Brumme,1,{dagger}* Chanson J. Brumme,1,{dagger} Jonathan Carlson,2,3,{dagger} Hendrik Streeck,1 Mina John,4 Quentin Eichbaum,1 Brian L. Block,1 Brett Baker,1 Carl Kadie,2 Martin Markowitz,5 Heiko Jessen,6 Anthony D. Kelleher,7 Eric Rosenberg,1 John Kaldor,7 Yuko Yuki,8 Mary Carrington,8 Todd M. Allen,1 Simon Mallal,4 Marcus Altfeld,1 David Heckerman,2 and Bruce D. Walker1,9

Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,1 Microsoft Research, Redmond, Washington,2 Department of Computer Science, University of Washington, Seattle, Washington,3 Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia,4 Aaron Diamond AIDS Research Center, New York, New York,5 Jessen Praxis, Berlin, Germany,6 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia,7 Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland,8 Howard Hughes Medical Institute, Chevy Chase, Maryland9

Received 18 May 2008/ Accepted 1 July 2008

During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in ~80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.

* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129-2000. Phone: (617) 643-2357. Fax: (617) 726-4691. E-mail: zbrumme{at}partners.org

{triangledown} Published ahead of print on 9 July 2008.

{dagger} These authors contributed equally to this work.

Journal of Virology, September 2008, p. 9216-9227, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.01041-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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