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

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. After introduction of combination antiretroviral therapy (cART), life expectancy has increased for people living with HIV (PLWHIV) 1-3 , 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. The majority of PLWHIV are coinfected with CMV, a common β-herpes virus that establishes lifelong latent infection with frequent asymptomatic reactivations 8. In PLWHIV, the presence of CMV coinfection has been associated with increased risk of inflammation, phenotypic T-cell alterations, and non-AIDS comorbidities 9-15. CMV seropositivity in PLWHIV have been associated with expansion of CD8+ T-cells, a reduced CD4+/CD8+ T-cell ratio, and increased levels of CD8+ T-cell senescence markers 9,10,12,14,16. Characteristics that independently have been associated with increased morbidity and mortality 17-19. The immunological mechanisms are incompletely understood, and it has been suggested that not only CMV infection itself but also the host's immune