T-Cell Activation Independently Associates With Immune Senescence in HIV-Infected Recipients of Long-term Antiretroviral Treatment

Abstract

Abstract Background.  Aging-associated noncommunicable comorbidities are more prevalent among human immunodeficiency virus type 1 (HIV)–infected individuals than among HIV-uninfected individuals. Residual HIV-related chronic immune activation and senescence may increase the risk of developing comorbidities. Methods.  Immune phenotyping, thymic output, and telomere length were assessed in 94 HIV-infected individuals who were aged >45 years and receiving antiretroviral therapy (ART; cases) and 95 age-matched uninfected controls. Results.  Cases had lower CD4+ T-cell counts, higher CD8+ T-cell counts, and increased levels of immune activation (ie, increased soluble CD14 [sCD14] level and increased percentages of CD38+HLA-DR+ cells among both CD4+ and CD8+ T cells), regulatory T cells, and percentage of programmed cell death 1 (PD-1)–expressing cells among CD4+ T cells. Immune senescence levels (ie, percentages of CD27−CD28− cells or CD57+ cells) were comparable between cases and controls. Peripheral blood mononuclear cells from cases had shorter telomeres but increased single-joint T-cell receptor excision circle content and CD31+ naive CD4+ T cells. Although cytomegalovirus (CMV) antibody titers were higher in cases, CMV-specific T-cell responses were comparable between cases and controls. T-cell senescence in cases was independently associated with T-cell activation but not with CMV-specific immune responses. Conclusions.  Despite long-term receipt of ART, HIV-infected adults had higher levels of immune activation, regulatory T cells, and PD-1–expressing CD4+ cells and shorter telomeres. The increased soluble CD14 levels and percentage of CD38+HLA-DR+ cells among CD4+ T cells correlated with shorter telomeres and increased regulatory T-cell levels. This suggests that HIV influences immune function irreversibly, with several pathways that are persistently abnormal during effective ART. Therapies aimed at improving immune health during ART are needed.