Background:  The cohort of individuals infected with HIV-1 is progressively aging, due, in large part, to the prolonged survival resulting from ART. HIV disease is comprised of several immune system changes that mirror those occurring during normal aging, suggesting possible synergistic immunological defects in older HIV⁺ individuals, consistent with the observed age-related, accelerated HIV disease progression. One of the salient features of the aging immune system, in the absence of HIV, is the accumulation of clonal expansions of CD8⁺ T cells with features of replicative senescence, including reduced proliferative capacity and effector function, shortened telomeres, loss of telomerase activity, absence of the CD28 co-stimulatory receptor, and altered cytokine profiles. Many of these T cells are specific for latent herpes viruses, particularly cytomegalovirus (CMV), suggesting that long-term maintenance of immunity to persistent viruses leads to the accumulation of dysfunctional virus-specific cells, which fail to be eliminated from the system. In the elderly, high proportions of senescent CD8⁺ T cells are associated with poor vaccine responses, osteoporotic bone disease, and early mortality.  In HIV-infected persons, both CMV and HIV-specific CD8⁺ T cells have also undergone extensive cell division, as indicated by their shortened telomeres, reduced antiviral function, and absence of CD28.

Methods:  To address the problem of CD8⁺ T cell exhaustion in both aging and AIDS, our laboratory has tested several approaches to retard or prevent the process of replicative senescence.

Results:  Experiments using gene transduction of CD8⁺ T cells from HIV-infected persons have provided proof-of-principle demonstration that maintenance of high constitutive telomerase activity is associated with increased proliferative potential, telomere length stabilization, and augmented anti-viral activity, with no evidence of karyotypic changes.  Similar effects are seen following exposure to a small-molecule telomerase activator, TAT2, which leads to significant increases in proliferation, production of anti-viral cytokines/chemokines, and capacity to limit viral production by HIV-infected autologous CD4⁺ T cells. 

Conclusions:  These telomerase-based approaches, and others involving  maintenance of CD28 expression, may lead to practical therapeutic strategies for preventing immune exhaustion in both young and progressively increasing population of older HIV-infected persons.