Background: HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naive T-cell numbers, elevated T-cell turnover, senescence, and inflammation.
Methods: Blood samples from immune failures (n = 60), immune successes (n = 20), and healthy controls (n = 20) were examined for plasma interleukin (IL)-7 levels, for cellular expression of the IL-7Rα chain (CD127), for the exhaustion and senescence markers programed death 1 (PD-1) and CD57, and for the survival factor Bcl2. Because both inflammatory and homeostatic cytokines can induce T-cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers.
Results: Plasma levels of IL-7 were elevated and both CD4 and CD8 T-cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naive CD4 T-cell counts in immune success and inversely with T-cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T-cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, whereas the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory IL-1β or homeostatic (IL-7) cytokines.
Conclusions: Perturbation of the IL-7/IL-7 receptor axis, increased T-cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients.