HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy

Stevenson, Eva M.; Ward, Adam R.; Truong, Ronald; Thomas, Allison S.; Huang, Szu-Han; Dilling, Thomas R.; Terry, Sandra; Bui, John K.; Mota, Talia M.; Danesh, Ali; Lee, Guinevere Q.; Gramatica, Andrea; Khadka, Pragya; Alberto, Winiffer D. Conce; Gandhi, Rajesh T.; McMahon, Deborah K.; Lalama, Christina M.; Bosch, Ronald J.; Macatangay, Bernard; Cyktor, Joshua C.; Eron, Joseph J.; Mellors, John W.; Jones, R. Brad

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed 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 reducing 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. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.