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

Beatriz Mothe,Bonaventura Clotet,Jennifer Zamarreño,Vanessa Bach,Anuska Llano,David Heckerman,Cristina Miranda,Guadalupe Gómez,Morgane Rolland,Susana Pérez-Álvarez,Bruce D Walker ,Marcus G Daniels ,James Szinger ,Otto O Yang ,M Farfán ,William H Hildebrand ,Rosario Zuñiga ,James I Mullins ,Víctor Sánchez-Merino ,Christoph T Berger ,José M Gatell ,Javier Martínez-Picado ,Jorge Sánchez ,Philip Goulder ,F Javier Ibarrondo ,Todd M Allen ,Bette T Korber ,Zabrina L Brumme ,María C Puertas ,Chanson J Brumme ,Christian Berthou

doi:10.1186/1479-5876-9-208

Abstract

BackgroundThe 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.MethodsHere, 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.ResultsFor 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.ConclusionsThe data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

Highlights

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
The current view on what may constitute a protective cellular immune response to HIV-1 is likely biased towards a immunodominant responses and those restricted by frequent HLA class I alleles and HLA alleles associated with superior disease outcome
HIV-1-specific T cell responses targeting conserved regions are associated with lower viral loads In a first analysis, HIV-1-specific T cell responses were assessed in a cohort of 223 HIV-1 clade B infected individuals recruited in Lima, Peru using IFNg ELISpot assays and a previously described set of 410 clade B overlapping peptides (OLP) [14,31]

Summary

Introduction

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. HIV-1 infection induces strong and broadly directed HLA class I restricted T cell responses for which specific epitopes and restricting HLA class I alleles have been associated with relative in vivo viral control [1]. CTL escape and viral fitness studies have focused largely on Gag-derived epitopes presented in the context of protective HLA class I alleles such as HLA-B27 and -B57 [7,20,21], yielding results that may not be generalizable to the genetically diverse majority of the human population. Many studies have focused on immunodominant targets only, despite some studies in HIV-1 and SIV infection demonstrating a crucial contribution of sub-dominant responses to targets outside of Gag to the effective in-vivo viral control [4,22]. The current view on what may constitute a protective cellular immune response to HIV-1 is likely biased towards a immunodominant responses and those restricted by frequent HLA class I alleles and HLA alleles associated with superior disease outcome

Methods

Results

Conclusion