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Journal of Virology, October 2002, p. 10155-10168, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10155-10168.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Magnitude and Frequency of Cytotoxic T-Lymphocyte Responses: Identification of Immunodominant Regions of Human Immunodeficiency Virus Type 1 Subtype C

V. Novitsky,1 H. Cao,2 N. Rybak,1 P. Gilbert,3 M. F. McLane,1 S. Gaolekwe,4 T. Peter,5 I. Thior,5 T. Ndung'u,1 R. Marlink,1 T. H. Lee,1 and M. Essex1*

Harvard School of Public Health, Boston, Massachusetts,1 Viral and Rickettsial Disease Laboratory, Department of Health Services, Richmond, California,2 University of Washington, Seattle, Washington,3 National Health Laboratory/National Blood Transfusion Center,4 Botswana-Harvard Partnership for HIV Research and Education, Gaborone, Botswana5

Received 29 March 2002/ Accepted 27 June 2002

A systematic analysis of immune responses on a population level is critical for a human immunodeficiency virus type 1 (HIV-1) vaccine design. Our studies in Botswana on (i) molecular analysis of the HIV-1 subtype C (HIV-1C) epidemic, (ii) frequencies of major histocompatibility complex class I HLA types, and (iii) cytotoxic T-lymphocyte (CTL) responses in the course of natural infection allowed us to address HIV-1C-specific immune responses on a population level. We analyzed the magnitude and frequency of the gamma interferon ELISPOT-based CTL responses and translated them into normalized cumulative CTL responses. The introduction of population-based cumulative CTL responses reflected both (i) essentials of the predominant virus circulating locally in Botswana and (ii) specificities of the genetic background of the Botswana population, and it allowed the identification of immunodominant regions across the entire HIV-1C. The most robust and vigorous immune responses were found within the HIV-1C proteins Gag p24, Vpr, Tat, and Nef. In addition, moderately strong responses were scattered across Gag p24, Pol reverse transcriptase and integrase, Vif, Tat, Env gp120 and gp41, and Nef. Assuming that at least some of the immune responses are protective, these identified immunodominant regions could be utilized in designing an HIV vaccine candidate for the population of southern Africa. Targeting multiple immunodominant regions should improve the overall vaccine immunogenicity in the local population and minimize viral escape from immune recognition. Furthermore, the analysis of HIV-1C-specific immune responses on a population level represents a comprehensive systematic approach in HIV vaccine design and should be considered for other HIV-1 subtypes and/or different geographic areas.

* Corresponding author. Mailing address: Department of Immunology and Infectious Diseases, Harvard School of Public Health, FXB-402, 651 Huntington Ave., Boston, MA 02115. Phone: (617) 432-0975. Fax: (617) 739-8348. E-mail: messex{at}hsph.harvard.edu.

Journal of Virology, October 2002, p. 10155-10168, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10155-10168.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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