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

Antonella Tripiciano, Orietta Picconi, Sonia Moretti, Cecilia Sgadari, Aurelio Cafaro, Vittorio Francavilla, Angela Arancio, Giovanni Paniccia, Massimo Campagna, Maria Rosaria Pavone-Cossut, Laura Sighinolfi, Alessandra Latini, Vito S Mercurio, Massimo Di Pietro, Francesco Castelli, Annalisa Saracino, Cristina Mussini, Giovanni Di Perri, Massimo Galli, Silvia Nozza, Fabrizio Ensoli, Paolo Monini, Barbara Ensoli, Antonella Tripiciano, Orietta Picconi, Sonia Moretti, Cecilia Sgadari, Aurelio Cafaro, Vittorio Francavilla, Angela Arancio, Giovanni Paniccia, Massimo Campagna, Maria Rosaria Pavone-Cossut, Laura Sighinolfi, Alessandra Latini, Vito S Mercurio, Massimo Di Pietro, Francesco Castelli, Annalisa Saracino, Cristina Mussini, Giovanni Di Perri, Massimo Galli, Silvia Nozza, Fabrizio Ensoli, Paolo Monini, Barbara Ensoli

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.

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Dynamics of immune parameters over 3 years of follow up in participants stratified by anti-Tat antibodies or cellular immune responses to Tat. CD4+ T cells, CD8+ T cells and CD4+/CD8+ T-cell ratio over time were analysed according to anti-Tat humoral and cellular responses in a longitudinal regression analysis for repeated measures using a mixed model with random-effects; N = 95 anti-Tat Ab−, 23 anti-Tat Ab+, 40 infrequent responders, 48 frequent responders. (a, b, c) CD4+ T-cell dynamics over time. (a) Regression analysis of the whole study population (β = 0.028 cells/day, p = 0.0125); (b) Participants stratified by humoral responses to Tat (anti-Tat Ab+: β = 0.09 cells/day, p < 0.0001; anti-Tat Ab−: β = 0.01 cells/day, p = 0.4326); (c) Volunteers stratified by cellular immune responses to Tat (frequent responders: β = 0.03 cells/day, p = 0.0242; infrequent responders: β = 0.01 cells/day, p = 0.6146). (d, e, f) CD8+ T-cell kinetics. (d) Regression analysis of the whole study population (β = -0.051 cells/day, p = 0.0265) (e) Regression analysis according to anti-Tat humoral responses (anti-Tat Ab+: β = 0.04 cells/day, p = 0.4045; anti-Tat Ab−: β = -0.08 cells/day, p = 0.0022); (f) Analysis according to cellular immune responses to Tat (frequent responders: β = -0.06 cells/day, p = 0.0739; infrequent responders: β = -0.07 cells/day, p = 0.0248); (g, h, i) CD4+/CD8+ T-cell ratio dynamics over time. (g) Regression analysis of the whole study population (β = 0.0002 cells/day, p < 0.0001) (h) Participants stratified by anti-Tat humoral responses (anti-Tat Ab+: β = 0.0002/day, p < 0.0001; anti-Tat Ab−: β = 0.0001/day, p < 0.0001); (i) Participants stratified by cellular immune responses (frequent responders: β=0.00015/day, p < 0.0001; infrequent responders β = 0.00016/day, p < 0.0001). β: slope of the regression line; p-values: probability β ≠ 0.
Fig. 2
Fig. 2
Volunteers’ immunological dynamics according to Tat humoral and cellular responses. Summary of the results of longitudinal regression analysis of immune-cell variations over time in volunteers cross-stratified for Tat serostatus and frequency of cellular responses to Tat. Dark green with arrow pointing upwards: significant increase over time; light green with arrow pointing downwards: significant decrease along time; intermediate green and absence of arrow: non-significant variations. CD4+ and CD8+ T cells in anti-Tat Ab+ infrequent responders showed non-significant increases and decreases, respectively, resulting in a significant increase of the CD4+/CD8+ T-cell ratio over time (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).
Fig. 3
Fig. 3
Residual viremia over 3 years of follow up in participants stratified by anti-Tat antibodies or cellular immune responses to Tat. Percentages of individuals that remained persistently aviremic (VL = undetectable) or had episodes of transient residual viremia (VL ≤ 40 HIV-1 RNA copies/mL) or viral blips (VL > 40 HIV-1 RNA copies/mL) during the study. (A) Participants stratified by anti-Tat humoral response (p = 0.0037) (anti-Tat Ab−: VL = undetectable: n. 31; VL ≤ 40: n. 30; VL > 40: n.34; anti-Tat Ab+: VL = undetectable: n. 14; VL ≤ 40: n. 0; VL > 40: n. 9); (B) Participants stratified by frequency of cellular responses to Tat (p = 0.7730) (infrequent responders: VL = undetectable: n.12; VL ≤ 40: n. 10; VL > 40: n.18; frequent responders: VL = undetectable: n. 16; VL ≤ 40: n. 14; VL > 40: n. 18). A chi-square test was utilized.

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