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Journal of Virology, April 2004, p. 3233-3243, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3233-3243.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hierarchical Targeting of Subtype C Human Immunodeficiency Virus Type 1 Proteins by CD8+ T Cells: Correlation with Viral Load

Agatha Masemola,1,{dagger} Tumelo Mashishi,1,{dagger} Greg Khoury,1 Phineas Mohube,1 Pauline Mokgotho,1 Efthyia Vardas,2,3 Mark Colvin,2 Lynn Zijenah,4 David Katzenstein,5 Rosemary Musonda,6 Susan Allen,6 Newton Kumwenda,7 Taha Taha,7 Glenda Gray,3 James McIntyre,3 Salim Abdool Karim,2,8 Haynes W. Sheppard,9 Clive M. Gray,1* and the HIVNET 028 Study Team{ddagger}

National Institute for Communicable Diseases,1 Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg,3 HIV Vaccine and Prevention Trials Unit, MRC,2 University of KwaZulu Natal, Durban, South Africa,8 Department of Immunology, University of Zimbabwe, Harare, Zimbabwe,4 Center for AIDS Research, Stanford University Medical Center, Stanford,5 California Department of Health Sciences, Richmond, California,9 Zambia-UAB HIV Research Project, Lusaka, Zambia,6 Johns Hopkins Research Project, Blantyre, Malawi7

Received 15 August 2003/ Accepted 21 November 2003

An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

* Corresponding author. Mailing address: National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, South Africa. Phone: 27 11386 6372. Fax: 27 11386 6310. E-mail: cgray{at}nicd.ac.za.

{dagger} A.M. and T.M. contributed equally to this work.

{ddagger} Contributing members of the HIVNET 028 Study Team are listed in Acknowledgments.

Journal of Virology, April 2004, p. 3233-3243, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3233-3243.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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