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Open Access Research

Definition of the viral targets of protective HIV-1-specific T cell responses

Beatriz Mothe123, Anuska Llano1, Javier Ibarrondo1, Marcus Daniels4, Cristina Miranda2, Jennifer Zamarreño1, Vanessa Bach1, Rosario Zuniga5, Susana Pérez-Álvarez16, Christoph T Berger7, Maria C Puertas1, Javier Martinez-Picado18, Morgane Rolland9, Marilu Farfan5, James J Szinger4, William H Hildebrand10, Otto O Yang11, Victor Sanchez-Merino12, Chanson J Brumme13, Zabrina L Brumme1314, David Heckerman15, Todd M Allen7, James I Mullins16, Guadalupe Gómez16, Philip J Goulder1718, Bruce D Walker18197, Jose M Gatell12, Bonaventura Clotet12, Bette T Korber204, Jorge Sanchez5 and Christian Brander18*

Author Affiliations

1 Irsicaixa AIDS Research Institute-HIVACAT, Badalona, Spain

2 'Lluita contra la SIDA' Foundation, Hospital Germans Trias i Pujol, Badalona, Spain

3 Universitat Autònoma de Barcelona, Barcelona, Spain

4 Los Alamos National Laboratory, Los Alamos, NM, USA

5 Asociación Civil IMPACTA Salud y Educacion, Lima, Peru

6 Dept. Estadística i Investigació Operativa, Universitat Politècnica de Catalunya, Barcelona, Spain

7 Ragon Institute of MGH, Harvard and MIT, Boston, MA, USA

8 Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

9 MHRP, Frederick, USA

10 University of Oklahoma Medical Center, Oklahoma City, OK, USA

11 University of California, Los Angeles, CA, USA

12 Services of Immunology and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS)-AIDS Research Group-HIVACAT, Hospital Clinic, Barcelona, Spain

13 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada

14 Simon Fraser University, Burnaby, BC, Canada

15 Miscrosoft Research, Redmond, WA, USA

16 Department of Microbiology, University of Washington, Seattle, WA, USA

17 Department of Paediatrics, Nuffield Department of Medicine, Oxford, UK

18 University of KwaZulu-Natal, HIV Pathogenesis Program, DDMRI, Durban, South Africa

19 Howard Hughes Medical Institute, Chevy Chase, MD, USA

20 Santa Fe Institute, Santa Fe, NM, USA

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Journal of Translational Medicine 2011, 9:208  doi:10.1186/1479-5876-9-208

Published: 7 December 2011

Abstract

Background

The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.

Methods

Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.

Results

For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.

Conclusions

The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

Keywords:
HIV specific CTL; clade B; clade C; HLA; vaccine immunogen design; functional avidity; epitope; entropy; immune correlate