Anti-Tat immunity defines CD4 + T-cell dynamics in people living with HIV on long-term cART.

Background: Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4 ⁺ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4 ⁺ T-cell dynamics has not yet been defined.
Methods: Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4 ⁺ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations.
Findings: Anti-Tat immunity is significantly associated with higher nadir CD4 ⁺ T-cell numbers, control of low-level viremia and long-lasting CD4 ⁺ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4 ⁺ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8 ⁺ T cells and B cells. Anti-Env immunity was not related to CD4 ⁺ T-cell recovery.
Interpretation: Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART.
Trial Registration: ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 FUNDING: Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020.
Competing Interests: Declaration of Competing Interest M. Di Pietro reports grants received from the Azienda Sanitaria of Florence during the conduct of the study. The other authors declares no conflict of interest.
(Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)