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Interdisciplinary Evaluation of Broadly-Reactive HLA Class II Restricted Epitopes Eliciting HIV-Specific CD4+T Cell Responses : Abstract of poster presentation

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Abstract

Background: CD4+ T cells orchestrate immune protection by ‘‘helping’’ other cells of our immune system to clear viral infections. It is well known that the preferential infection and depletion of CD4+ T cells contributes to hampered systemic T cell help following HIV infection. However, the functional and immunodominant discrepancies of CD4+ T cell responses targeting promiscuous MHC II restricted HIV epitopes remains poorly defined. Thus, utilization of interdisciplinary approaches might aid revealing broadly- reactive peptides eliciting CD4 + T cell responses. Methods: We utilized the novel bioinformatic prediction program NetMHCIIpan to select 64 optimized MHC II restricted epitopes located in the HIV Gag, Pol, Env, Nef and Tat regions. The epitopes were selected to cover the global diversity of the virus (multiple subtypes) and the human immune system(diverse MHC II types). Optimized polychromatic flow cytometry analysis, including the functional markers IFNc, IL-2, IL-21, MIP-Ib and TNFa, revealed immunogenicity of the individual epitopes. The study subjects (n = 38) were of diverse ethnical background infected by different HIV subtypes. High resolution HLA typing and sequences of the HIV-Gag and Nef regions were obtained. Results: The FACS analysis revealed immunogenicity against 73% of the epitopes. All subjects, except one, recognized at least one epitope. Interestingly, almost all epitopes located in Gag (15/ 15) and Nef (14/15) elicited responses, while epitopes in Pol (10/ 15) and Env (5/15) revealed restricted CD4 + T cell immunogenicity. This difference in immunogenicsity between the regions was significant (One-way ANOVA: p <0.001). Additionally, Gag and Nef epitopes generated greater polyfunctionality than Poland Env-specific CD4+ T cells. Importantly, we found that the use of optimized epitopes improved the polyfunctionality compared with overlapping HIV Gag (p55) peptides. Conclusion: Using an unbiased approach where we have predicted peptides with same prerequisites, we demonstrate that HIV-specific CD4 + T cell immunodominance is heavily skewed, targeting particularly Gag and Nef.