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.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV Infections/virology , HIV-1/immunology , Host-Pathogen Interactions/immunology , tat Gene Products, Human Immunodeficiency Virus/immunology , Antiretroviral Therapy, Highly Active , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Biomarkers , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , HIV Antibodies/immunology , HIV Infections/drug therapy , Humans , Immunophenotyping , Lymphocyte Activation , Viral LoadABSTRACT
BACKGROUND: Baseline and follow-up predictors of new AIDS-defining events or death (ADE/death) among patients who started HAART late in their disease history have rarely been assessed simultaneously. METHOD: ADE and mortality rates were assessed using Cox regression analyses. Variables were tested for prediction of ADE/death within the first 3 months of therapy and from month 3, thereafter. RESULTS: 751 HIV-infected patients with <200 CD4+/mm(3) before HAART were followed for a median of 49 months. 207 new ADE occurred (7.06 [6.16-8.10] per 100 patient-years). ADE/deaths clustered within the first 3 months of treatment (106/207, 51%). Higher CD4+ T-cell counts during the follow-up (per log(e) cells/mm(3): hazard ratio [HR] 0.51; 0.41-0.64; p < .001) and use of antiretroviral therapy (HR 0.38; 95% CI 0.21-0.69; p = .001) appeared to protect from ADE/death after month 3. Conversely, increasing follow-up with HIV RNA >400 copies/mL correlated with ADE/death (per month: HR 1.09; 95% CI 1.06-1.12; p = .001). Use of boosted protease inhibitors as first-line HAART and HCV-seropositivity were additional risk factors. Baseline CD4+ T-cell count and HIV RNA had a predominant impact in the first 3 months after HAART initiation. CONCLUSION: A careful monitoring of patients with low CD4+ is particularly necessary during the first few months of HAART. Length and extent of viral replication during the follow-up appeared to induce a significantly higher risk of HIV disease progression afterwards, implying that new drugs and new strategies aimed at ensuring long-term suppression of HIV RNA are of outstanding importance.
