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Journal of Virology, August 2009, p. 7641-7648, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00182-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1-Specific CD8⁺ T-Cell Responses during Primary Infection Are Major Determinants of the Viral Set Point and Loss of CD4⁺ T Cells ^,

Hendrik Streeck,¹ Jonathan S. Jolin,¹ Ying Qi,³ Bader Yassine-Diab,² Randall C. Johnson,³ Douglas S. Kwon,¹ Marylyn M. Addo,¹ Chanson Brumme,¹ Jean-Pierre Routy,⁴ Susan Little,⁵ Heiko K. Jessen,⁶ Anthony D. Kelleher,⁷ Frederick M. Hecht,⁸ Rafick-Pierre Sekaly,² Eric S. Rosenberg,¹ Bruce D. Walker,^1,9 Mary Carrington,³ and Marcus Altfeld^1*

Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,¹ Laboratoire d'Immunologie, Centre de Recherche du CHUM, Montreal, Quebec, Canada,² Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland,³ McGill University, Division of Hematology and Immunodeficiency Service, Royal Victoria Hospital, Montreal, Quebec, Canada,⁴ Department of Medicine, University of California, San Diego, San Diego, California,⁵ HIV Clinic Praxis Jessen, Berlin, Germany,⁶ National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Darlinghurst, Australia,⁷ Department of Medicine, San Francisco General Hospital, University of California, San Francisco, San Francisco, California,⁸ Howard Hughes Medical Institute, Chevy Chase, Maryland⁹

Received 26 January 2009/ Accepted 12 May 2009

Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8⁺ T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4⁺ T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8⁺ T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4⁺ T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines.

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* Corresponding author. Mailing address: Ragon Institute of MGH, MIT, and Harvard, 149 13th Street, Boston, MA 02129. Phone: (617) 724-2461. Fax: (617) 724-8586. E-mail: maltfeld{at}partners.org

Published ahead of print on 20 May 2009.

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

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Journal of Virology, August 2009, p. 7641-7648, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00182-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.