Evaluating potential T-cell epitope peptides for detecting HIV-specific T cell responses in a highly diverse HIV-1 epidemic from Cameroon

Abstract

HIV genetic diversity is a major obstacle for vaccine development. To define whether potential Tcell epitope (PTE) peptide usage improves the detection of T cell responses in a highly diverse HIV-1 epidemic, we compared the magnitude, breadth and depth of group M PTE peptide responses to consensus M peptides in Gag and Nef proteins. Gag PTE responses were detected at a higher magnitude, more Nef PTE responses were detected at a cohort (but not individual) level, and depth was detected in both Gag and Nef responses.The genetic diversity of HIV represents a major challenge for the development of a universal HIV vaccine. One approach that has been developed to deal with this variability is 'mosaic' vaccine immunogens, representing sets of bioinformatically-designed sequences that attempt to maximize coverage of HIV diversity [1][2][3]. By including multiple variants for a particular epitopic region, PTE peptides are designed to increase immunological recognition of HIV. Studies in non-human primates have shown that mosaic immunogens improved the breadth and depth of cellular immune responses to globally circulating HIV-1 strains compared to consensus and natural antigens [4,5] Data from this study were presented previously at the Keystone Symposia, Banff, Alberta, Canada, March 8-14, 2014; Poster Number: 3051. Conflict of interestThere are no conflicts of interest. Testing the recognition of variant peptide sets containing 'potential T cell epitopes' (PTE peptides) based on mosaic vaccines in HIV-infected individuals represents a proxy (albeit with significant limitations) for the potential cross-reactivity of mosaic immunogens to viruses circulating in a given population [7]. To date, group M PTE peptides have not been evaluated for recognition in a highly diverse HIV-1 epidemic, such as west central Africa, which is home to virtually all HIV-1 subtypes and many circulating and unique recombinant forms (CRF and URF) [8,9]. We previously characterized the high diversity of circulating strains in HIV-1-infected blood donors from Cameroon and evaluated cellular HIV responses [8,10]. Here, we assessed the recognition of PTE peptides based on mosaic group M sequences compared to consensus (CON) group M sequences in this group. Both sets of peptides were obtained from the NIH AIDS Reagent Program (https:// www.aidsreagent.org), and CON M peptides were based on the 2001 HIV-1 group M consensus sequences from the Los Alamos National HIV sequence database, which included pure clades and recombinant forms. Europe PMC Funders GroupWe measured IFN-γ responses by ELISPOT to two 15-mer peptide panels: HIV-1 group M CON peptides spanning Gag (129 peptides) and Nef proteins (53); and group M PTE peptides for Gag (320) or Nef (127), including 0-6 variants (median 1) per epitopic region.To identify positive responses, PTE peptides were screened in pools arranged using the software "Deconvolute This" (Mario Roederer, Vaccine Research Center, NIH), in which each individual Gag and Nef peptide appeared 3-4 times; the CON set w...

Challenges in the Design of a T Cell Vaccine in the Context of HIV-1 Diversity

“…Recognition of multiple variants was detected with the PTE peptide set, with up to five variants being recognized for particular peptides. This was more pronounced in Gag where out of the total peptides targeted, 60% had also at least one variant recognized [ 124 ]. This underscores the fact that there are fewer characterized epitopes from the diverse set of viruses circulating in Cameroon and in west central Africa present in HIV sequence databases, so if a mosaic approach for an HIV-1 vaccine is pursued, or the use of PTE peptides for vaccine testing is implemented, additional mosaic sequences may need to be included for greater coverage in highly diverse epidemics.…”