Abstract
Resting CD4+ T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition of the ability of a subset of elite controllers (EC) to control virus without therapy due to robust anti-HIV immune responses. Controllers have low levels of integrated HIV DNA and low levels of replication competent virus, suggesting a small reservoir. As our recent data indicates some reservoir cells can produce HIV proteins (termed GPR cells for Gag-positive reservoir cells), we hypothesized that a fraction of HIV-expressing resting CD4+ T cells could be efficiently targeted and cleared in individuals who control HIV via anti-HIV cytotoxic T lymphocytes (CTL). To test this we examined if superinfected resting CD4+ T cells from EC express HIV Gag without producing infectious virus and the susceptibility of these cells to CTL. We found that resting CD4+ T cells expressed HIV Gag and were cleared by autologous CD8+ T cells from EC. Importantly, we found the extent of CTL clearance in our in vitro assay correlates with in vivo reservoir size and that a population of Gag expressing resting CD4+ T cells exists in vivo in patients well controlled on therapy.
Highlights
Resting CD4+ T cells harboring latent proviruses remain barriers to a cure for HIV [1,2,3,4,5,6]
We show for the first time that effective cytotoxic T lymphocytes (CTL) can clear resting CD4+ T cells expressing Gag in vitro and that this ability correlates with in vivo reservoir size
Even non-controllers well suppressed on anti-viral therapy (ART) have GPR cells detectable in vivo that could be targeted by the immune system, even without other activating agents such as vorinostat
Summary
Resting CD4+ T cells harboring latent proviruses remain barriers to a cure for HIV [1,2,3,4,5,6]. We recently reported, using an in vitro model of latency, that resting CD4+ T cells can produce HIV Gag without any stimulation and without producing infectious virus [21]. These prior observations, along with evidence that a subset of EC have a strong anti-Gag CD8+ T cell response associated with an overrepresentation of particular “protective” HLA class I alleles (B-57 and B-27) [22,23], led to our hypothesis that Gagpositive reservoir cells (GPR cells) are susceptible to cytotoxic T lymphocyte (CTL) mediated elimination in controllers, resulting in lower reservoir size. Our study provides important insight into how CTL might limit reservoir size
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