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Journal of Virology, May 2004, p. 4463-4477, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4463-4477.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Comprehensive Analysis of Human Immunodeficiency Virus Type 1-Specific CD4 Responses Reveals Marked Immunodominance of gag and nef and the Presence of Broadly Recognized Peptides

Daniel E. Kaufmann,1 Paul M. Bailey,1 John Sidney,2 Bradford Wagner,1 Philip J. Norris,1 Mary N. Johnston,1 Lisa A. Cosimi,3 Marylyn M. Addo,1 Mathias Lichterfeld,1 Marcus Altfeld,1 Nicole Frahm,1 Christian Brander,1 Alessandro Sette,2 Bruce D. Walker,1,4 and Eric S. Rosenberg1*

Partners AIDS Research Center and Infectious Disease Unit,1 Howard Hughes Medical Institute, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02114,4 Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115,3 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 921212

Received 11 August 2003/ Accepted 5 January 2004

Increasing evidence suggests that human immunodeficiency virus type 1 (HIV-1)-specific CD4 T-cell responses contribute to effective immune control of HIV-1 infection. However, the breadths and specificities of these responses have not been defined. We screened fresh CD8-depleted peripheral blood mononuclear cells (PBMC) from 36 subjects at different stages of HIV-1 infection for virus-specific CD4 responses by gamma interferon enzyme-linked immunospot assay, using 410 overlapping peptides spanning all HIV-1 proteins (based on the clade B consensus sequence). HIV-1-specific CD4 responses were identified in 30 of the 36 individuals studied, with the strongest and broadest responses detected in persons treated in acute infection who underwent treatment interruption. In individuals with identified responses, the total number of recognized HIV-1 peptides ranged from 1 to 36 (median, 7) and the total magnitude of responses ranged from 80 to >14,600 (median, 990) spot-forming cells/106 CD8-depleted PBMC. Neither the total magnitude nor the number of responses correlated with viremia. The most frequent and robust responses were directed against epitopes within the Gag and Nef proteins. Peptides targeted by >=25% of individuals were then tested for binding to a panel of common HLA-DR molecules. All bound broadly to at least four of the eight alleles tested, and two bound to all of the HLA-DR molecules studied. Fine mapping and HLA restriction of the responses against four of these peptides showed a combination of clustering of epitopes and promiscuous presentation of the same epitopes by different HLA class II alleles. These findings have implications for the design of immunotherapeutic strategies and for testing candidate HIV vaccines.

* Corresponding author. Mailing address: Infectious Disease Division, Massachusetts General Hospital, Gray J-504, 55 Fruit St., Boston, MA 02114. Phone: (617) 724-7519. Fax: (617) 726-3795. E-mail: erosenberg1{at}partners.org.

Journal of Virology, May 2004, p. 4463-4477, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4463-4477.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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