4.7 Article

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

Journal

PLOS PATHOGENS
Volume 13, Issue 9, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1006629

Keywords

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Funding

  1. National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1AI126617]
  2. National Institute on Drug Abuse
  3. National Institute of Mental Health
  4. National Institute of Neurological Disorders and Stroke
  5. National Institute of Allergy and Infectious Diseases [UM1 AI068636]
  6. National Institute of Mental Health (NIMH)
  7. National Institute of Dental and Craniofacial Research (NIDCR)
  8. AIDS Clinical Trials Group Network (ACTG)
  9. District of Columbia Center for AIDS Research
  10. NIH [AI117970]
  11. NIH
  12. NIAID
  13. NCI
  14. NICHD
  15. NHLBI
  16. NIDA
  17. NIMH
  18. NIA
  19. FIC
  20. NIGMS
  21. NIDDK
  22. OAR

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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-gamma-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.

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