Abstract
BackgroundNone of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs.MethodsTo overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1.ResultsOur approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4+ and CD8+ T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4+ and CD8+ T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ+ CD8+ T cells being Granzyme B+ and able to degranulate (CD107a+).ConclusionsThese data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0392-5) contains supplementary material, which is available to authorized users.
Highlights
None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity
Design of the HIVACAT T-cell immunogen (HTI) covering targets of effective antiviral T cell responses We recently reported a systematic analysis of a large set of human immune data from cohorts of HIV-1 infected individuals [27,28,36]
18-mer overlapping peptides (OLP) spanning the entire viral proteome, 26 consensus clade B derived OLP were identified for which the median viral load in the OLP responder group was significantly lower than the viral load in subjects who did not target these OLP (i.e., OLP nonresponders)
Summary
None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. CD8+ cytotoxic T lymphocytes (CTL) responses to HIV-1 Gag have most consistently been associated with reduced viral loads in both HIV-1 clade B- and C-infected cohorts [2,4] This is in line with data from post-hoc analyses of the STEP vaccine trial, where individuals in whom vaccine-induced responses targeted ≥3 different Gag epitopes achieved a lower viral load than subjects without Gag responses [5]. CD4+ T-cell responses to Gag have been associated with relative HIV-1 control [6,7] It remains unclear whether the relative benefit of Gag is due to high protein expression levels, rapid representation of viral particle-derived CTL epitopes [8], reduced susceptibility of Gag-specific CTL to Nef-mediated immune evasion strategies [9] or particular amino acid composition and inherently greater immunogenicity [10]. Effective vaccine design should probably aim to induce broad and evenly distributed responses to conserved and vulnerable sites of the virus while avoiding the induction of responses to regions that can be highly immunogenic but that may act as potential “decoy” targets and divert responses away from more relevant targets [17,18,19,20,21,22]
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