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

Abstract

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.

Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size

“…Our cohort-based analysis also found no evidence that COVID-19 mRNA vaccination induced changes in HIV reservoir size, nor in total, 5'-defective, or 3'-defective proviral loads. This is consistent with findings from of three studies that assessed smaller numbers of participants for this outcome using similar approaches [27,29,31].…”

“…Taken together with similar findings from other studies [27][28][29]31], we conclude that there is now a strong body of evidence indicating COVID-19 immunization is safe and effective in PWH [4][5][6][7][8][9][10][11][12]. This should provide additional reassurance to PWH and their care providers regarding the safety of COVID-19 mRNA vaccines.…”

“…The mass rollout of COVID-19 mRNA vaccines provided an opportunity to study the potential stimulatory effects of this new vaccine modality on the HIV reservoir. Though a number of studies have now investigated this topic [27][28][29]31], their results have not been entirely conclusive. While one study found evidence of a gradual, though not statistically significant increase in the rate of detectable viremia peaking 4 weeks after the second vaccine dose [27], two others reported no changes in viremia following two-dose vaccination [28,30].…”

Immunologic Interplay Between HIV/AIDS and COVID-19: Adding Fuel to the Flames?

“…In this context, the increased HIV transcription is accompanied by enhanced HIV-specific CD8 + T-cell responses, pointing to standard vaccines as a potential tool to reverse HIV latency to enable eradication by cytotoxic T-cells [ 93 ]. Accordingly, a recent study showed that BNT162b2 vaccine activates the RIG-I/TLR–TNF–NFkB axis, resulting in transcription of HIV proviruses; in parallel, Nef-specific CD8 + T-cells increase and acquire cytotoxic effector functions, which correlate with reduction of cell-associated HIV-mRNA, suggesting killing or suppression of cells transcribing HIV; however, significant depletion of intact proviruses was not observed, highlighting challenges to achieving HIV reservoir reductions [ 94 •]. Nevertheless, the interplay between vaccines, immune system, and latent HIV infection is yet to be thoroughly understood and deserves further research in order to inform future HIV eradication strategies.…”

HIV and COVID-19 Co-Infection: Epidemiology, Clinical Characteristics, and Treatment

“…However, it has recently been reported that following SARS-CoV-2 mRNA vaccination, a transient HIV expression occurs, manifesting primarily as the activation of HIV-Nef-specific CD8+ T-cell responses. Even though researchers have not observed a significant depletion of intact proviruses, this CD8+ T-cell induction is correlated with significant decreases in cell-associated HIV mRNA, suggesting the killing or suppression of cells transcribing HIV [ 155 ]. Some mRNA vaccines targeting HIV antigens are under development for both prophylactic and therapeutic settings.…”