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]

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Summary

Introduction

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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