HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy
Eva M. Stevenson, Adam R. Ward, Ronald Truong, Allison S. Thomas, Szu-Han Huang, Thomas R. Dilling, Sandra Terry, John K. Bui, Talia M. Mota, Ali Danesh, Guinevere Q. Lee, Andrea Gramatica, Pragya Khadka, Winiffer D. Conce Alberto, Rajesh T. Gandhi, Deborah K. McMahon, Christina M. Lalama, Ronald J. Bosch, Bernard Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, R. Brad Jones, for the AIDS Clinical Trials Group A5321 Team
Eva M. Stevenson, Adam R. Ward, Ronald Truong, Allison S. Thomas, Szu-Han Huang, Thomas R. Dilling, Sandra Terry, John K. Bui, Talia M. Mota, Ali Danesh, Guinevere Q. Lee, Andrea Gramatica, Pragya Khadka, Winiffer D. Conce Alberto, Rajesh T. Gandhi, Deborah K. McMahon, Christina M. Lalama, Ronald J. Bosch, Bernard Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, R. Brad Jones, for the AIDS Clinical Trials Group A5321 Team
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Research Article AIDS/HIV Immunology

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

Abstract

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.

Authors

Eva M. Stevenson, Adam R. Ward, Ronald Truong, Allison S. Thomas, Szu-Han Huang, Thomas R. Dilling, Sandra Terry, John K. Bui, Talia M. Mota, Ali Danesh, Guinevere Q. Lee, Andrea Gramatica, Pragya Khadka, Winiffer D. Conce Alberto, Rajesh T. Gandhi, Deborah K. McMahon, Christina M. Lalama, Ronald J. Bosch, Bernard Macatangay, Joshua C. Cyktor, Joseph J. Eron, John W. Mellors, R. Brad Jones, for the AIDS Clinical Trials Group A5321 Team

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Figure 3

HIV-specific T cell responses are highly stable on long-term ART, with HIV Nef-specific response dynamics uniquely associated with reservoir measures.

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HIV-specific T cell responses are highly stable on long-term ART, with H...
(A) Participant-specific slopes of change in T cell responses from week 24 to week 168 after study entry. P values represent the significance level for the covariate time (in weeks) in linear mixed-effects models from Supplemental Table 3. (B) Correlogram depicting Spearman’s correlations between slopes of change in raw magnitudes of T cell responses (from panel A) with virologic and immunologic parameters. Color scale bar represents magnitude of correlation coefficient. Circle size represents unadjusted P values, corrected for the false discovery rate. Asterisks represent adjusted P values: for HIV DNA controlling for pre-ART plasma HIV RNA, pre-ART CD4+ T cell count, and years on ART at study entry, and pre-ART plasma HIV RNA controlling for HIV DNA at study entry; all adjusted P values are corrected for the false discovery rate (*P < 0.05).