Background:  Apoptosis is considered one of the primary mechanisms of CD4⁺ T-cell depletion during the course of HIV-1 infection. Thus, therapeutic strategies that reduce apoptosis should prolong T-cell survival and facilitate immune reconstitution in HIV-1-infected subjects.

Methods:  Apoptosis levels were studied in peripheral blood mononuclear cells (PBMC) and purified CD4⁺ and CD8⁺ T-cell subsets obtained from 29 HIV-1-infected subjects at different stages of disease and 14 HIV-1-seronegative controls. Apoptosis levels were measured daily for 7 days of ex vivo culture by evaluating Annexin-V binding, propidium-iodide staining, and caspase-3 activation. Cellular proliferation was assessed by Ki67 staining, CFSE dilution, and absolute cell counting; HIV-1 replication was determined by p24 antigen release. Recombinant human interleukin-7 (IL-7) was added at the onset of culture.

Results:  Levels of spontaneous apoptosis over 7 days of ex vivo culture were significantly higher in HIV-1-infected subjects than in HIV-1-seronegative controls (p <0.0001). Treatment with IL-7 at 0.5-5.0 ng/mL exerted significant anti-apoptotic effects on PBMC from HIV-1-infected subjects (p <0.0001), but not from seronegative controls. The degree of apoptosis reduction was inversely correlated with the number of circulating CD4⁺ T cells, indicating a higher sensitivity to IL-7 effects in patients with more advanced disease. Analysis of purified CD4⁺ and CD8⁺ T cells demonstrated that both subsets were sensitive to the protective effects of IL-7. The anti-apoptotic effect of IL-7 was uncoupled from the induction of cellular proliferation. Moreover, at doses that reduced apoptosis, IL-7 did not trigger or increase the levels of endogenous HIV-1 replication.

Conclusions:  The anti-apoptotic activity of IL-7 documented in HIV-1-infected subjects provides a further rationale for consideration of this cytokine as an agent of immune reconstitution in HIV-1 infection.