Abstract
CD4+ T cells orchestrate immunity against viral infections, but their importance in HIV infection remains controversial. Nevertheless, comprehensive studies have associated increase in breadth and functional characteristics of HIV-specific CD4+ T cells with decreased viral load. A major challenge for the identification of HIV-specific CD4+ T cells targeting broadly reactive epitopes in populations with diverse ethnic background stems from the vast genomic variation of HIV and the diversity of the host cellular immune system. Here, we describe a novel epitope selection strategy, PopCover, that aims to resolve this challenge, and identify a set of potential HLA class II-restricted HIV epitopes that in concert will provide optimal viral and host coverage. Using this selection strategy, we identified 64 putative epitopes (peptides) located in the Gag, Nef, Env, Pol and Tat protein regions of HIV. In total, 73% of the predicted peptides were found to induce HIV-specific CD4+ T cell responses. The Gag and Nef peptides induced most responses. The vast majority of the peptides (93%) had predicted restriction to the patient’s HLA alleles. Interestingly, the viral load in viremic patients was inversely correlated to the number of targeted Gag peptides. In addition, the predicted Gag peptides were found to induce broader polyfunctional CD4+ T cell responses compared to the commonly used Gag-p55 peptide pool. These results demonstrate the power of the PopCover method for the identification of broadly recognized HLA class II-restricted epitopes. All together, selection strategies, such as PopCover, might with success be used for the evaluation of antigen-specific CD4+ T cell responses and design of future vaccines.
Highlights
The cellular immune response represents a crucial component of the battle against viral infections, including that of human immunodeficiency virus type 1 (HIV)
We developed a novel algorithm, PopCover, that takes into consideration both host and viral variability to identify HIV-Gag, -Pol, -Env, -Nef and -Tat peptides restricted to multiple HLA-DR and –DQ alleles
To enable the identification of broadly reactive HLA class IIrestricted peptides, and the patterns of immunodominance and functionality, a diverse patient cohort infected with multiple viral subtypes was identified
Summary
The cellular immune response represents a crucial component of the battle against viral infections, including that of human immunodeficiency virus type 1 (HIV). CD4+ T cells are critical for maintaining and mobilising the adaptive immune response, essentially providing helper functions to different arms of the response. The borderline protection provided by the canarypox-gp120 combination in the RV144 vaccine trial [6] called further attention to HIV-specific CD4+ T cell responses as one of few possible correlates of vaccine protection. Comprehensive analyses have shown that Gag-specific CD4+ T cell responses dominate the total pool of HIV-specific CD4+ T cells [7,8], and increased frequencies of these cells have been associated with lower viral loads in HIV-infected individuals [8,9]
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