Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses

Abstract

Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called “beneficial” regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.

Adenovirus-based HIV-1 vaccine candidates tested in efficacy trials elicit CD8+ T cells with limited breadth of HIV-1 inhibition

“…The present report demonstrated that Gag and Pol were the predominant HIV-1 proteins recognised by CD8 Tcells in both Ad5 regimen vaccinees and HIV-1 infected subjects. The correlation between the number of peptide pools recognized by CD8 Tcells and breadth of VIA (Fig 2B) supports the strategy that T-cell based vaccines should aim to increase the number of HIV-1 epitopes targeted by T-cells thereby potentially enhancing vaccine efficacy [58].The present report agrees with a report[59] describing inhibitory abilities of CD8 T-cells isolated directly from PBMC from HIV-1 infected STEP vaccinees (MRKAd5) where inhibition would be due to a combination of vaccination and natural infection. Inhibition breadth was narrow and inferior to chronically infected viremic controllers (pVL <5000/mL).However, PBMC availability limited the number of isolates tested in the majority of vaccinees to 3 or 4.…”

Evaluation of the immunogenicity and impact on the latent HIV‐1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy‐treated subjects

“…T cells must also be able to recognize the epitopes generated by reactivated cells during a short window and ideally target regions of vulnerability that are known to lead to loss of viral fitness upon CD8+ T cell attack in vivo [36]. Some of these regions were not included in the HIVconsv immunogen because they were not highly conserved; refinement of the immunogen design may be necessary to ensure boosting of the most potent CD8+ T cell responses [30,[37][38][39][40]. Analysis of the HLA class I-associated peptidome could facilitate this as we have recently shown, using tandem mass spectrometry, that the HLA class I-associated HIV-1 peptidome on primary CD4+ T cells includes a substantial proportion of epitopes that had not been described previously [41].…”

The Safety and Immunogenicity of an Interleukin-12–Enhanced Multiantigen DNA Vaccine Delivered by Electroporation for the Treatment of HIV-1 Infection

“…Nonetheless, it is conceivable that performing the ICC assays focused on “beneficial peptides” found to be associated with ex vivo viral inhibition, or performing the viral inhibition assay itself, could have produced different results. 30,31 …”