Introduction
Treatment of HIV-infected patients with combination antiretroviral therapy (ART) has led to a significant reduction in both morbidity and mortality. Therefore, HIV infection has transitioned from an acute, terminal illness to a chronic but manageable condition [1]. While this is undoubtedly a major success, several studies have demonstrated that HIV-infected individuals are at an increased risk of age-related non-AIDS morbidity and mortality compared with uninfected persons [2]. These observations have led to the proposal that HIV-infected individuals suffer from accelerated or premature aging [3]. However, the pathogenic mechanisms underlying this increased aging process remain poorly understood.
Growing evidence suggests that immune exhaustion and senescence caused by HIV infection is similar to that caused by age in uninfected elderly subjects [4-6]. During nature aging, a reduction in T cell renewal occurs together with a progressive enrichment of terminally differentiated T cells with shortened telomeres. It is thought that these changes are the consequence of immune activation and inflammation, which translates into a general decline of the immune system, which gradually leads to immunosenescence (aging of the immune system) [7]. Similarly, high levels of systemic immune activation and inflammation due to HIV infection promote the accelerated replicative senescence of T cells [8], which leads to an imbalance of T cell phenotype [9,10]. This results in the differentiation and accumulation of nonfunctional senescent T cells [6]. In addition, studies have shown that premature and accelerated T cell aging in HIV-infected patients can be caused by the adverse effects of antiretroviral drugs [11,12]. Hopefully, data from a recent clinical study convincingly suggest that the initiation of ART can lead to rapid improvements in several clinical outcomes [13,14]; however, the extent to which these immunological signatures were restored during ART has not been determined. Moreover, little is known about the combined impact of HIV infection and ART drugs on immunosenescence in HIV-infected individuals.
Although some reports have characterized distinct T cell subsets in HIV-infected subjects and compared their distribution with those in healthy subjects [15,16], few data are available regarding the activation/senescent profile in relation to the immunosenescence features of distinct T cell subsets. In addition, no reports have provided a comprehensive assessment of telomere length of distinct T cell subsets, of which telomere shortening represents a key molecular marker of biological aging. In the current study, we provide a detailed characterization of biological aging in relation to immune senescence and activation markers of the different CD4+ T cell subsets in a cohort of male homosexual HIV-infected subjects, including ART-naive and ART-treated subjects.