SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8 T-cells
Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8 cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8 T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8 T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.
Stevenson, Eva M.; Terry, Sandra; Copertino, Dennis; Leyre, Louise; Danesh, Ali; Weiler, Jared; Ward, Adam R.; Khadka, Pragya; McNeil, Evan; Bernard, Kevin; Miller, Itzayana G.; Ellsworth, Grant B.; Johnston, Carrie D.; Finkelsztein, Eli J.; Zumbo, Paul; Betel, Doron; Dündar, Friederike; Duncan, Maggie C.; Lapointe, Hope R.; Speckmaier, Sarah; Moran-Garcia, Nadia; Papa, Michelle Premazzi; Nicholes, Samuel; Stover, Carissa J.; Lynch, Rebecca M.; Caskey, Marina; Gaebler, Christian; Chun, Tae-Wook; Bosque, Alberto; Wilkin, Timothy J.; Lee, Guinevere Q.; and Brumme, Zabrina L., "SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8 T-cells" (2022). GW Authored Works. Paper 1462.
Microbiology, Immunology, and Tropical Medicine