Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis.

Introduction: Residual immune dysfunctions, resembling those that occur during normal aging, may persist even in well-treated people with HIV (PWH), and accelerated aging has been proposed. We aimed to determine if HIV infection is an independent risk factor for T-cell immune dysfunctions including increased immune activation, senescence and apoptosis. Moreover, in PWH we aimed to identify the associations between age and immune activation, senescence and apoptosis. Materials and Methods: We included 780 PWH with suppressed viral replication (<50 copies/mL) and absence of hepatitis B and hepatitis C co-infection and 65 uninfected controls from the Copenhagen Co-morbidity in HIV Infection (COCOMO) Study. Flow cytometry was used to determine T-cell activation (CD38+HLA-DR+), senescence (CD28-CD57+), and apoptosis (CD28-CD95+). T-cell subsets are reported as proportions of CD4+ and CD8+ T-cells. We defined an elevated proportion of a given T-cell subset as above the 75th percentile. Regression models were used to determine the association between HIV status and T-cell subset and in PWH to determine the association between age or HIV-specific risk factors and T-cell subsets. Furthermore, an interaction between HIV status and age on T-cell subsets was investigated with an interaction term in models including both PWH and controls. Models were adjusted for age, sex, BMI, and smoking status. Results: In adjusted models a positive HIV status was associated with elevated proportions of CD8+ activated (p = 0.009), CD4+ senescent (p = 0.004), CD4+ apoptotic (p = 0.002), and CD8+ apoptotic (p = 0.003) T-cells. In PWH a 10-year increase in age was associated with higher proportions of CD4+ and CD8+ senescent (p = 0.001 and p < 0.001) and CD4+ and CD8+ apoptotic T-cells (p < 0.001 and p < 0.001). However, no interaction between HIV status and age was found. Furthermore, in PWH a CD4+/CD8+ ratio < 1 was associated with elevated proportions of T-cell activation, senescence, and apoptosis. Discussion: We found evidence of residual T-cell immune dysfunction in well-treated PWH without HBV or HCV co-infection, and age was associated with T-cell senescence and apoptosis. Our data supports that HIV infection has similar effects as aging on T-cell subsets. However, since no interaction between HIV status and age was found on these parameters, we found no evidence to support accelerated immunological aging in PWH.

The impact of concurrent HIV and type II diabetes on immune maturation, immune regulation and immune activation.

Chronic immune activation and inflammation are constant findings in people living with HIV (PLWH) and contribute to the risk of non-AIDS-related morbidities, including cardiovascular diseases (CVD). Type 2 diabetes (T2D) is also characterized by immune activation and inflammation. We aimed to investigate the impact of concurrent HIV infection and T2D on T-cell subsets. The study included PLWH with T2D (HIV+T2D+, N = 25) and without T2D (HIV+T2D-, N = 25) and HIV-negative controls with T2D (HIV-T2D+, N = 22) and without T2D (HIV-T2D-, N = 28). All PLWH in the study were receiving combination antiretroviral therapy. We examined T-cell homeostasis by determining T-cell subsets (immune maturation, immune regulation and immune activation) using flow cytometry. HIV+T2D- had lower proportion of Tc17 cells and higher proportion of apoptotic cells than HIV-T2D-. When comparing HIV+T2D+ and HIV+T2D- a lower proportion of CD4+ recent thymic emigrants (RTE) was found (p = 0.028). Furthermore, HIV+T2D+ had a higher proportion of non-suppressive CD4+ Tregs compared to HIV+T2D- (p = 0.010). In conclusion, even in the setting of treated HIV infection, distinct immunological alterations are found. In PLWH with concomitant T2D, most alterations in T-cell subsets were related to HIV and only few differences were found between PLWH with and without diabetes.

HIV-Specific CD8+ T Cell-Mediated Viral Suppression Correlates With the Expression of CD57.

BACKGROUND: Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44 HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells. METHOD: Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-γ, interleukin-2, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1ß (MIP-1ß) responses to HIV-1 were evaluated by intracellular staining. The phenotypic profile of CD8(+) T cells was determined by whole blood staining. RESULTS: The expression of CD57 on effector CD8(+) T cells correlated with the suppression of HIV-1 replication and to the duration of ART. CD107a and tumor necrosis factor-α expression levels were significantly higher in individuals with ex vivo suppressive activity compared with individuals without suppressive activity. CONCLUSIONS: Standard in vitro assays measuring one or several cytokines do not correlate with the functional viral suppressive capacity of CD8(+) T cells from HIV-1-positive individuals. The best correlation of viral suppression was found to be CD57 expression. CD57 expression correlated with the duration of ART, suggesting that ART restores the cytotoxic capacity of CD8(+) T lymphocytes.