Short Conserved Sequences of HIV-1 Are Highly Immunogenic and Shift Immunodominance

Abstract

HIV-1 sequence diversity is a major barrier limiting the capability of cellular immunity to contain infection and the ability of vaccines to match circulating viral sequences. To date, vaccines tested in humans have delivered whole proteins or genes for whole proteins, and it is unclear whether including only conserved sequences would yield sufficient cellular immunogenicity. We tested a vaccine delivering genes for four small conserved HIV-1 regions compared to a control vaccine with genes for whole Gag, Env, and Nef. Although the conserved regions ranged from 43 to 86 amino acids and comprised less than one-fifth of the whole Gag/Env/Nef sequence, the vaccines elicited equivalent total magnitudes of both CD4+ and CD8+ T lymphocyte responses. These data demonstrate the immunogenicity of these small conserved regions and the potential for a vaccine to steer immunodominance toward conserved epitopes.

T cell-based strategies for HIV-1 vaccines

“…In contrast, CD8+ T-cell-directed vaccines can target more conserved protein regions with greater cross-reactive potential and for which escape has greater fitness costs; [16][17][18][19][20][21][22][23][24][25] moreover, vaccination can shift responses toward highly conserved epitopes that are infrequently presented in natural infection, which may be advantageous in a therapeutic setting. 16,18,24,26 In addition, a new type of T-cell-based vaccine modality is being explored based on the observation that non-classical MHC-E restricted CD8+ T-cell responses elicited by SIV antigens delivered in a modified cytomegalovirus vector can clear SIV infections in over half of vaccinated macaques in an SIV challenge model.…”

“…51 Vaccines with improved antigen design and delivery strategies can elicit higher numbers of responses 38,55 with greater crossreactive potential. 17,19,21,24,25,56 Furthermore, NHP SIV challenge studies have repeatedly found that CD8+ T-cell responses, particularly those targeting Gag, directly correlate with better viral control and survival. [57][58][59][60][61][62][63] Vaccine antigen designs to elicit enhanced CD8+ T-cell immune and humoral responses…”

“…Various strategies have been employed to improve CD8+ T-cell vaccine antigens. Contenders include (i) full-length mosaic proteins, designed to better cover viral epitope diversity than natural strains and to maximize the number of epitopes presented by many different HLAs by using full proteins (note that the mere number of T-cell epitopes targeted is often correlated with a beneficial effect in NHPs [36][37][38]55,58 ); (ii) concatenation of large conserved protein regions that still retain high numbers of PTEs, while minimizing unnatural junctions and excluding variable epitopes; 17,19,21 and (iii) multiple short peptides intended to more narrowly focus responses on preferred epitopes. 20,25,43,65,66 Figures 1-3 provide direct comparisons of vaccine candidates to illustrate differences in design strategy and in diversity coverage.…”

“…Mosaics can be full proteins 38,55 or span shorter protein regions. 19,21 The inclusion of multiple common epitope variants in mosaic vaccine cocktails has been shown experimentally to stimulate responses that recognize diverse natural forms of the epitope, sometimes beyond just those included in the vaccine cocktail. 38,56 We typically optimize mosaics for vaccine coverage of 9-mers, the most common length of a CD8+ T-cell epitope, 36 and also the length of the core interaction region between CD4+ T-cell epitopes and class II molecules.…”

“…Since even conserved regions of HIV are somewhat variable, two complementary global mosaics were designed to improve PTE coverage of the selected regions. (Yang and colleagues 21 used three mosaics to span the conserved regions they favored, instead of just twothe choice weighs vaccine complexity with more complete diversity coverage.) tHIVconsvX was highly immunogenic in mice, and in a Japanese treatment-naïve HIV+ population, natural responses to epitopes within the vaccine were associated with lower viral loads and higher CD4+ T-cell counts.…”