Dataset Information

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.

SUBMITTER: Tripiciano A

PROVIDER: S-EPMC8105504 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite the effectiveness of cART, people living with HIV still experience an increased risk of serious non-AIDS events, as compared to the HIV negative population. Whether pre-cART microbial translocation (MT) and systemic inflammation might predict morbidity/mortality during suppressive cART, independently of other known risk factors, is still unclear. Thus, we aimed to investigate the role of pre-cART inflammation and MT as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort.MethodsWe included Icona patients with ≥2 vials of plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale).ResultsWe studied 486 patients with 125 clinical events: 39 (31%) AIDS, 66 (53%) SNAEs and 20 (16%) deaths. Among the analyzed MT and pro-inflammatory markers, hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death) after adjustment for confounders, both when the study population was stratified according to the median of the distribution (1.51 mg/L) and when the study population was stratified according to the 33% percentiles of the distribution (low 0.0-1.1 mg/L; intermediate 1.2-5.3 mg/L; high > 5.3 mg/L). In particular, the higher the hs-CRP values, the higher the risk of clinical progression (p = 0.056 for median-based model; p = 0.002 for 33% percentile-based model).ConclusionsOur data carries evidence for an association between the risk of disease progression after cART initiation and circulating pre-cART hs-CRP levels but not with levels of MT. These results suggest that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation.

Project description:BackgroundAlthough tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer.MethodsTo evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A's function. In a translational approach, we validated activin-A's anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients.ResultsAdministration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells.ConclusionsIn this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

Dataset Information

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

Background

Methods

Findings

Interpretation

Trial registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Findings

Interpretation

Trial registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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