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.