Uncoupled anti-HIV and immune-enhancing effects when combining IFN-alpha and IL-7

Cytokine-based therapies have been examined for purging viral reservoirs and immunomodulation in HIV infection. However, single cytokines did not result in either HIV eradication or an efficient HIV-specific immune response. We hypothesize that cytokines with distinct biologic effects need to be combined for immunotherapy of HIV infection. In this study, we investigated the anti-HIV activity and immune-enhancing effects of the combination of IFN-alpha and IL-7. In human lymphocyte aggregate cultures infected ex vivo with the X4 HIV strain NL4-3, IFN-alpha/IL-7 potently inhibited HIV replication and preserved CD4(+) T cells, probably by up-regulating Bcl-2. IFN-alpha/IL-7 also strongly inhibited R5 HIV replication. Furthermore, in allogeneic MLRs, IFN-alpha/IL-7 increased T cell proliferation and IFN-gamma production. IFN-alpha alone also had strong anti-HIV activity, but neither preserved CD4(+) T cells nor increased T cell responses in MLRs. IL-7 alone maintained T cells and enhanced T cell activation in MLRs, but only moderately inhibited or increased HIV replication. Thus, coadministration of IFN-alpha/IL-7 combines the potent anti-HIV activity of IFN-alpha with the beneficial effects of IL-7 on T cell survival and function. We speculate that IFN-alpha will block viral replication, activate APCs, and up-regulate MHC molecules, thus allowing IL-7 to display its effects for generating an efficient immune response. In this scenario, the known reactivation of latent HIV by IL-7 may be advantageous.