Functional properties and epitope characteristics of T-cells recognizing natural HIV-1 variants

Abstract

To understand how broad recognition of HIV-1 variants may be achieved we examined T-cell reactivity in newly-infected persons as well as vaccine recipients to a broad spectrum of potential Tcell epitope (PTE) variants containing conservative, semi-conservative and non-conservative amino acid substitutions. Among early-infected persons T-cells recognized epitope variants with one substitution at a significantly higher frequency versus those with two (P=0.0098) and three (P=0.0125) substitutions. Furthermore T cells recognized variants containing conservative substitutions at a higher frequency versus those containing semi-conservative (P=0.0029) and nonconservative (P<0.0001) substitutions. Similar effects were observed on recognition of variants by vaccine induced T-cells. Moreover even when variants were recognized, the IFN-γ and granzyme B responses as well as T-cell proliferation were of lower magnitude. Finally, we show that epitope distribution is strongly influenced by both processing preferences and amino acid entropy. We conclude that induction of broad immunity is likely to require immunogen sequences that encompass multiple variants. However, cost-effective design of peptide and sequence based vaccine immunogens that provide maximal coverage of circulating sequences may be achieved through emphasis on virus domains likely to be T-cell targets.

Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study

“…Vaccine immunogenicity was measured on a subset of participants in the HVTN laboratory using a validated IFN-γ ELISPOT assay using two panels of peptide pools, Clade B vaccine-matched and Clade C potential T-cell epitopes (PTE-C), in previously cryopreserved PBMCs 22 . The primary immunogenicity assessment was conducted on samples obtained by venipuncture at Week 8, 4 weeks following the second vaccination from the first 186 participants enrolled (93 vaccinees/93 placebo recipients) who were HIV-1 antibody negative at the Week 12 visit; had received the second study injection, and whose thawed PBMC had ≥ 66% cell viability 23 .…”

Translation of HLA–HIV Associations to the Cellular Level: HIV Adapts To Inflate CD8 T Cell Responses against Nef and HLA-Adapted Variant Epitopes

“…Furthermore, we did not find that responses which appeared more inherently cross-reactive, as indicated by lack of match with autologous viral sequences were more likely to respond to the adapted epitopes. The general determinants of T cell recognition of viral variants have been explored in other studies (42, 43). It is important to emphasise we have tested specific epitope pairs based on population-signals of adaptation.…”

Targeting of Conserved Gag-Epitopes in Early HIV Infection Is Associated with Lower Plasma Viral Load and Slower CD4+T Cell Depletion

“…It is well known that recognition of antigen by the TCR is extremely sensitive. 10,11 However, there are regions in the HIV genome that are more conserved between the different strains and subtypes. 12 Mutations in more conserved regions tend to have a higher impact on fitness and reduce the viral replication.…”