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.