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.
Highlights
After introduction of combination antiretroviral therapy, life expectancy has increased for people living with HIV (PLWHIV)[1,2,3], but has not yet reached that of the background population[4]
In treated HIV infection, the magnitude of the CMV-specific immune response, defined by CMV immunoglobulin G (IgG) levels or CMV-specific T-cell responses, has been associated with phenotypic T-cell alterations[15,20,21,22,23], and non-AIDS comorbidity[24,25,26,27,28,29], suggesting that a dysfunctional control of CMV may contribute to the immune dysfunction and early onset of age-related comorbidity observed in PLWHIV despite treatment with combination antiretroviral therapy (cART)
In previous studies we found that PLWHIV had increased immune activation, inflammation, and microbial translocation compared to matched controls[30,31,32]
Summary
After introduction of combination antiretroviral therapy (cART), life expectancy has increased for people living with HIV (PLWHIV)[1,2,3], but has not yet reached that of the background population[4]. Non-AIDS comorbidity contributes to the gap in life expectancy, and PLWHIV on stable cART have increased risk for early onset of age-related diseases including cardiovascular diseases and renal diseases[5] This is probably due to complex interactions between HIV infection itself, traditional risk factors, and other factors such as coinfection with cytomegalovirus (CMV), residual immune dysfunction, and inflammation[6,7]. In treated HIV infection, the magnitude of the CMV-specific immune response, defined by CMV IgG levels or CMV-specific T-cell responses, has been associated with phenotypic T-cell alterations[15,20,21,22,23], and non-AIDS comorbidity[24,25,26,27,28,29], suggesting that a dysfunctional control of CMV may contribute to the immune dysfunction and early onset of age-related comorbidity observed in PLWHIV despite treatment with cART. We further evaluated whether PLWHIV maintain CMV-specific T-cell polyfunctionality, defined as single cells producing two or more cytokines, despite increased T-cell senescence and higher CMV-specific T-cell responses
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