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.
Highlights
Two HIV vaccines designed to elicit protective T cell responses have reached clinical efficacy testing, both with disappointing results [1][2][3]
We previously showed that the capacity of CD8+ T cells from patients to block HIV replication in culture is strongly correlated with HIV control in vivo, we investigated the virological determinants of potent CD8+ T cell inhibitory activity
We observed that CD8+ T cells from patients with naturally low plasma viral loads were better able to inhibit the replication of diverse HIV strains in vitro than CD8+ T cells from HIV-noncontroller patients
Summary
Two HIV vaccines designed to elicit protective T cell responses have reached clinical efficacy testing, both with disappointing results [1][2][3]. Gag proteins contained the majority of the beneficial regions, though not all of them, and contained regions that were not targeted by protective responses Together, these data support the ‘decoy’ hypothesis, which proposes that certain epitopes within the viral proteome elicit dominant yet irrelevant responses that serve to undermine effective targeting of regions of vulnerability [15]. These data support the ‘decoy’ hypothesis, which proposes that certain epitopes within the viral proteome elicit dominant yet irrelevant responses that serve to undermine effective targeting of regions of vulnerability [15] This question will only be adequately addressed by clinical testing of rationally designed immunogens based on ‘beneficial’ regions, as proposed by Rolland et al and Mothe et al [15][14]
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