Abstract
Antiretroviral therapies (ART) durably suppress HIV replication to undetectable levels – however, infection persists in the form of long-lived reservoirs of infected cells with integrated proviruses, that re-seed systemic replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in driving reductions in viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle, by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. We show that T-cell responses to autologous reservoir viruses persist over years, and that the maintenance of HIV-Nef-specific responses was uniquely associated with residual frequencies of infected cells. These responses disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV-infected cells. These results indicate substantial visibility of the HIV reservoir to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing HIV infection.
Competing Interest Statement
JWM is a consultant to Gilead Sciences and Merck, and owns share options in Co-Crystal Pharmaceuticals and Abound Bio, Inc., which are not involved in the current work. JJE has research funding outside the current work from ViiV Healthcare, Gilead Sciences and Janssen, and has consulting income from ViiV Healthcare, Gilead Sciences, Janssen, and Merck. BM has received research funding from Gilead Sciences. RTG has served on a scientific advisory board for Merck. EMS volunteers on the Board of Directors of the non-profit community clinic the Berkeley Community Health Project. The authors declare that they have no other perceived conflicts of interest.