T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy

PLoS Pathogens

Bruce D. Walker¹  Allison S. Thomas²  Ronald Truong²  Colin Kovacs²  Alberto Bosque²  Amanda B. Macedo²  Szu-Han Huang²  Kimberley L. Jones²  Ronald J. Bosch³  Joseph J. Eron³  Dora Chan⁴  R. Brad Jones⁴  Joshua C. Cyktor⁴  Christina M. Lalama⁵  Samuel Simmens⁵  Erika Benko⁶  Deborah K. McMahon⁷  John W. Mellors⁸  Rajesh T. Gandhi⁸ 

[1] Department of Epidemiology and Biostatistics, George Washington University, Milken Institute School of Public Health, Washington, District of Columbia, United States of America;Department of Microbiology Immunology and Tropical Medicine, George Washington University, Washington, District of Columbia, United States of America;Division of Infectious Diseases, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America;Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Harvard TH Chan School of Public Health, Boston, Massachusetts, United States of America;Maple Leaf Medical Clinic, Toronto, Canada;Massachusetts General Hospital, Boston, Massachusetts, United States of America;Ragon Institute of MIT, MGH, and Harvard, Cambridge MA, United States of America

关键词: T cells;    HIV;    Cytotoxic T cells;    Enzyme-linked immunoassays;    Antiretroviral therapy;    Gene pool;    Cloning;    Antigen processing;    recognition;   

DOI  :  10.1371/journal.ppat.1006629

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART), these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18). Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that enhancing the cytolytic activity of Nef-specific T-cells may lead to reductions in infected cell frequencies, even in the absence of therapeutic latency reversal.

【 授权许可】

CC BY