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

Abstract

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.

Keywords: Anti-Tat antibodies; Anti-Tat cellular immunity; CD4+ T cells; HIV immune activation; HIV reservoirs; HIV residual viremia; HIV-1 Tat; Perspective for clinical implications.