Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV

Abstract

In people living with HIV (PLWHIV), coinfection with cytomegalovirus (CMV) has been associated with inflammation, immunological ageing, and increased risk of severe non-AIDS related comorbidity. The effect of CMV-specific immune responses on systemic inflammation, immune activation and T-cell senescence was evaluated in 53 PLWHIV treated with combination antiretroviral therapy (cART). Activated-, terminally differentiated-, naïve-, and senescent T-cells were assessed by flow cytometry, and plasma levels of CMV IgG, interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein and soluble-CD14 were measured. In PLWHIV, expression of interleukin-2, tumor necrosis factor-α and interferon-γ was measured by intracellular-cytokine-staining after stimulation of T-cells with CMV-pp65, CMV-IE1, and CMV-gB. Increased CMV-specific T-cell responses were associated with a higher ratio of terminally differentiated/naïve CD8+ T-cells and with increased proportions of senescent CD8+ T-cells, but not with systemic inflammation or sCD14. Increased CMV-specific CD4+ T-cell responses were associated with increased proportions of activated CD8+ T-cells. In PLWHIV with expansion of CMV-specific T-cells or increased T-cell senescence, CMV-specific polyfunctionality was maintained. That the magnitude of the CMV-specific T-cell response was associated with a senescent immune phenotype, suggests that a dysregulated immune response against CMV may contribute to the immunological ageing often described in PLWHIV despite stable cART.

Cytomegalovirus-specific CD8+ T-cell responses are associated with arterial blood pressure in people living with HIV

“…A total of 60 PLHIV from the outpatient clinic at the Department of Infectious Diseases, Rigshospitalet, Copenhagen, were consecutively included in a study regarding cognitive function and cardiovascular risk profile, and 31 HIV-uninfected controls were selected for comparison and matched overall on age, gender, BMI, education and comorbidity index (assessed by the Charlson comorbidity index). Procedures for recruitment, data collection, demographics, and clinical characteristics of the participants have previously been described in detail [15,[35][36][37][38][39]. Nineteen of the controls also participated in a study on diabetes [40].…”

“…The method is a standardized and validated approach that has been used by multiple groups to determine ex vivo T-cell responses [44][45][46][47][48]. The method has been described in detail in a previous publication [15]. In CMV-seropositive PLHIV (n = 54), CMV-specific CD8+ and CD4+ T-cell responses were determined by measurement of intracellular expression of IL-2, TNF-α and IFN-γ after stimulation of peripheral blood mononuclear cells (PBMC) with CMV-pp65 and CMV-gB [15].…”

“…The method has been described in detail in a previous publication [15]. In CMV-seropositive PLHIV (n = 54), CMV-specific CD8+ and CD4+ T-cell responses were determined by measurement of intracellular expression of IL-2, TNF-α and IFN-γ after stimulation of peripheral blood mononuclear cells (PBMC) with CMV-pp65 and CMV-gB [15]. We used the CFC Becton Dickinson assay that has been optimized by the manufacturer and with a recommended stimulation time of 6 hours (BD Bioscience) [46].…”

“…Cytokine responses were acquired immediately using a BD FACSCanto™ II flow cytometer and flow cytometry results were analysed using BD FACSDiva (v8.0.1) software (BD Biosciences). The gating strategy has previously been described [15]. In brief, a lymphocyte gate based on FSC/SSC, a singlet gate, and a live/dead cell gate were applied before gating on CD3+CD4+ and CD3+CD8+ cells.…”

“…CMV is a human β-herpesvirus with a world-wide distribution and a high prevalence in most populations [12,13]. The majority of PLHIV are infected with CMV, and PLHIV have higher T-cell and antibody-specific responses against CMV than HIV-uninfected [14,15]. CMV has been linked to increased risk of CVD-related morbidity and mortality in PLHIV [16], and increased magnitude of CMV-specific immune responses have been associated with subclinical cardiovascular disease [17][18][19].…”