SARS-CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8+ T cells

BACKGROUND: SARS-CoV-2 mRNA vaccines activate TLR and inflammatory signaling pathways, and thus may activate transcription from HIV proviruses. We hypothesized that, in addition to virological measures, a key manifestation of this would bein vivoboosting of T-cell responses specific for the early gene product HIV-Nef. This was based upon our previously reported findings that Nef-specific T-cells disproportionately recognize residual antigen expression during long-term antiretroviral therapy (ART), enforcing an effector profile (granzyme-B release).
METHODS: HIV RNA in PBMC supernatants was measured by RT-qPCR. T-cell responses to HIV gene products were measured at baseline and ~2 weeks after SARS-CoV-2 mRNA vaccine prime and boost in 13 ART-treated adults using IFN-gor granzyme-B ELISPOT, as well as activation induced marker (AIM) assays. Total and unspliced HIV mRNA, as well as intact and defective (IPDA) HIV DNA were measured in parallel by digital droplet PCR (ddPCR).
RESULTS: Treatment of PBMCs from ART-treated donors with SARS-CoV-2 mRNA vaccines drove release of HIV RNA into supernatants (n=6, p=0.03). Within days of vaccinations, we observed transientin vivoincreases in cell-associated HIV RNA. Nef-specific T-cell responses increased following vaccine-prime by granzyme-B ELISPOT (3.1-fold increase, p=0.002), with a parallel trend by AIM assay (1.5-fold, p=0.06). Analogous increases were not observed in responses to late gene products. Unspliced and total HIV mRNA decreased modestly between baseline and 2 weeks post vaccine-boost, unspliced-1.6-fold decrease p=0.03; total-1.5-fold decrease p=0.05. Changes in total HIV mRNA showed strong inverse correlations with Nef-specific granzyme B-producing (spearman'sr=-0.73, p=0.006) and Nef-specific CD8+ AIM T-cell responses (r=-0.76, p=0.006) following vaccine prime. Neither total nor intact HIV DNA changed significantly across the study.
CONCLUSIONS: SARS-CoV-2 mRNA vaccination induced a degree of HIV latency reversal, resulting in engagement of HIV-Nef-specific CD8+ T-cells with a cytotoxic profile. The strong correlations between increases in these responses and subsequent decreases in cell-associated HIV RNA suggest some elimination of transcriptionally-active cells. However, this was not accompanied by reductions in intact or total HIV DNA. This may reflect that only a minority of proviruses were responsible for transcription, both at baseline and following latency reversal, consistent with recent observations in the field.