Discussion
Chronic HIV infection can drive premature T cell aging, even in the setting of ART with complete viral suppression. In this study, we demonstrate that male homosexual HIV subjects exhibit premature biological aging with accelerated immune senescence, which affects CD4+ T cell subsets that have partial recovery by ART.
In the context of HIV infection, disruption of normal T cell homeostasis has been observed when a massive and continuous depletion of CD4+ T cells occurs. Compared with healthy age-matched subjects, a lower [15] or similar [16] CD4+naive T cell frequency has been reported. As expected, the results of this study show a lower CD4+ naive T cell frequency in HIV-infected subjects compared with healthy subjects. This may be partially explained by the capacity of the thymus to produce new T cells or thymic output, which is significantly decreased during the course of HIV infection [22-24]. Overall, the frequency of naive T cells represents a good marker of immunological age in humans, and its progressive decrease in HIV-infected adults is typically directly associated with HIV disease progression [25]. A significant increase in memory cell populations is observed when compared to the uninfected controls in our study, especially in TEM, which is consistent with a previous report [26]. Moreover, ART treatment result in a partial restoration of the pool of naive as well as memory T cells, which show an increase in naive T cells and a reduction of TEM and TemRA cell populations, although a return to normal levels has seldom been observed. Overall, our data support a notion in which active HIV replication drives the production of a senescent phenotype, resulting in a decline in T cell competence.
CD57 has been described as a marker of replicative senescence in T cells, and is associated with telomere shortening following numerous cell divisions [19]. Interestingly, this marker, along with the marker of T cell activation (HLA-DR), is recently used to assess immune activation and senescence, which is correlated with the clinical status of HIV-infected patients and is closely associated with the increase in non-AIDS-related morbidities (e.g., cardiovascular disease, chronic liver disease, kidney disease, osteoporosis, neurocognitive disease, and cancer) in HIV-suppressed patients with age < 60 years old [27]. In our study, we observe higher CD57 and HLA-DR expression in the expanded CD4+ memory T cell populations in HIV-infected subjects, with the exception of naive T cells. However, the decreased levels of specific CD4+ T cell subsets may reflect the effect of ART that can reduce CD4+ T cell activation [28]. Moreover, immune senescence is greater in HIV-infected subjects with detectable HIV viremia. This indicates that active HIV replication leads a senescent phenotype, which demands for the early control of HIV replication and chronic immune activation. Of note, despite effective suppression of viral replication, ART fails to re-establish immunological homeostasis in the treated patients, which is indicative of a fully exhausted phenotype.
Telomeres play an important role in controlling both cultured cell senescence in vitro and the aging process in vivo[29]. As a classical marker of cell senescence, the shortening of telomere length is often used as an indicator of individual biological age [30]. Some reports [31,32] have analyzed telomere length, which is usually measured in total PBMCs or total T cell subsets (CD4 or CD8), demonstrating that telomere length was shorter in HIV-infected individuals compared to age-matched seronegative controls. This suggests that there is accelerated immunological aging with HIV infection. During the course of HIV infection, the distribution of CD4 cell subsets is known changed, and telomere length is also varied in distinct cell subsets according to the stage of differentiation (e.g., naive and memory cells). To date, there is limited data available regarding the telomere length of distinct T cell subsets. In our study, no significant differences are observed in telomere length of naive T cells between HIV-infected subjects and healthy controls. Consistent with a previous report [33], we also find that ART had no obvious effect on the telomere length of naive T cells, which indicates that either HIV infection or exposure to ART had little influence on naive T cells. However, ART-naive subjects had significantly shorter telomeres in memory T cells compared to healthy controls and those HIV subjects on ART, indicating that HIV infection, rather than exposure to ART, affects the aging process. However, it has been reported that ART may inhibit telomerase activity, leading to differences in telomere lengths between the ART-naive and ART-treated groups. Previous studies have inconsistent findings in such an association [34-36]. Therefore, a further comprehensive analysis of telomere length in different T cell subsets in accordance with the stage of T cell differentiation, the effect of ART on telomere length, and potential mechanisms are required in future.
In this study, we analyzed the immunosenescence of CD4+ T cell subsets in male homosexual patients with HIV-1 infection. Unfortunately, our current cohort is too small to stratify CD4+T cells in patients receiving antiretroviral therapy for their CD4+ T cell nadir.
In conclusion, male homosexual subjects with HIV-1 infection exhibit premature aging with accelerated immune senescence, which affects the CD4+ T cell subsets. The higher expression of senescent markers on different CD4+ T cell subsets in ART-naive subjects, compared with ART-receiving subjects or healthy controls, suggests that HIV infection, rather than ART exposure, influences the aging process. Our data support the importance of early HIV control to avoid premature immune senescence to reduce the risk of age-related diseases, including malignancies. Our findings can also be interpreted as a correlation between CD4+ T cell senescence and premature aging of the immune system, which can continue to be observed despite successful viral suppression.