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

Eva M. Stevenson,¹ Adam R. Ward,² Ronald Truong,² Allison S. Thomas,³ Szu-Han Huang,² Thomas R. Dilling,¹ Sandra Terry,¹ John K. Bui,¹ Talia M. Mota,¹ Ali Danesh,¹ Guinevere Q. Lee,¹ Andrea Gramatica,¹ Pragya Khadka,¹ Winiffer D. Conce Alberto,¹ Rajesh T. Gandhi,⁵ Deborah K. McMahon,⁶ Christina M. Lalama,⁷ Ronald J. Bosch,⁷ Bernard J. Macatangay,⁶ Joshua C. Cyktor,⁶ Joseph J. Eron,⁸ John W. Mellors,⁶ and R. Brad Jones¹

Published January 5, 2021 - More info

Antiretroviral therapies (ART) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which re-seed 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.

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