ABSTRACT
Background: The kinetics and functional profiles (granzyme-B production) of HIV-specific T-cell responses support that those targeting the early viral gene product Nef disproportionately recognize residual antigen expression during long-term antiretroviral therapy (ART). Here, we leveraged this insight to test whether SARS-CoV2 mRNA vaccines-which activate TLR and inflammatory signaling pathways-would reactivate latent HIV, stimulating T-cell responses with these characteristics. Methods: T-cell responses to individual HIV gene products were measured by IFN-g or granzyme B ELISPOT, and by activation induced marker (AIM) assays at baseline and ∼2 weeks after SARS-CoV-2 mRNA vaccine prime and boost, in 13 long-term ART treated adults. Total and unspliced HIV mRNA, as well as intact and defective (IPDA) HIV DNA were measured in parallel by digital droplet PCR (ddPCR). Results: We observed transient increases Nef-specific T-cell responses following vaccine prime by granzyme B ELISPOT (3.1-fold increase, p=0.002) and a trend by AIM assay (1.5-fold increase, p=0.06). Such increases were not observed in granzyme B responses to late gene products nor in any IFN-g responses. Both unspliced and total HIV mRNA decreased significantly across the study, unspliced-1.6-fold decrease p = 0.03;total-1.5-fold decrease p = 0.05. Changes in total HIV mRNA correlated inversely with Nef-specific granzyme B-producing (spearman's ρ =-0.73, p = 0.006) and Nef-specific CD8+ AIM T-cell responses (ρ =-0.76, p = 0.006) following vaccine prime. These reductions in HIV RNA were not accompanied by significant changes in total or intact HIV DNA. Conclusion: Consistent with our hypothesis, a restricted profile of HIV-specific T-cell responses showed significant increases following SARS-CoV-2 vaccine prime, each of which were then correlated with reductions in HIV RNA. This supports that vaccination promoted productive interactions between Nef-specific CTL and HIV-infected cells in vivo. We propose three scenarios for why this was not reflected in reductions in intact or total HIV DNA: i) meaningful depletions in inducible proviruses occurred but were lost against the background of non-inducible proviruses ii) interactions with CTL involved only a fraction of inducible proviruses, or iii) substantive proviral depletions occurred, but were counterbalanced by clonal expansion of HIV-infected cells.
ABSTRACT
The 2021 Conference on Retroviruses and Opportunistic Infections included advances in therapy for HIV as well as for SARS-CoV-2. Data presented on COVID-19 therapies included trials showcasing the use of monoclonal antibodies for prevention and treatment of COVID-19. Promising new data were presented on lenacapavir, an investigational HIV capsid inhibitor given as a subcutaneous injection every 6 months. Although encouraging data from settings across the globe reported achievement of 90-90-90 HIV care cascade targets, disparities exist in care engagement and viral suppression, particularly for people of color and young people with HIV. Several interventions were associated with improved care cascade outcomes. The COVID-19 pandemic has impacted HIV care engagement, but mitigation strategies can allow programs to continue to serve people with HIV during the pandemic. Studies examining the resistance patterns of existing antiretroviral therapy (ART) agents were presented, as were resistance mechanisms of novel agents such as lenacapavir and resistance patterns among individuals who seroconverted while on preexposure prophylaxis. Data from large observational cohorts were presented on patterns of ART uptake and trends in mortality and in virologic failure. Pertinent findings relating to pediatric and maternal health issues included data on dolutegravir-based ART in children and adolescents with HIV;safety and tolerability of dolutegravir-based ART in children and pregnant women;similarly high maternal viral suppression at 50 weeks postpartum in women receiving certain ART regimens;weight gain in pregnant women receiving dolutegravir plus tenofovir alafenamide/emtricitabine;and viral suppression with dolutegravir-based ART when started during the third trimester of pregnancy.