INDUCTION OF HIV-1 REPLICATION IN LATENTLY INFECTED CD4(-CELLS USING A COMBINATION OF CYTOKINES() T)

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in p eripheral blood mononuclear cells (PBMCs) of HIV-1-infected individual s, it is unclear what role these cytokines play in the induction of HI V-1 replication in latently infected, resting CD4(+) T cells. This stu dy demonstrates that the in vitro combination of the proinflammatory c ytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha toge ther with the immunoregulatory cytokine IL-2 are potent inducers of vi ral replication in highly purified, latently infected, resting CD4(+) T cells derived from HIV-infected individuals who are antiretroviral t herapy-naive as well as those who are receiving highly active antiretr oviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vit ro. Given that an array of cytokines, including IL-6, TNF-alpha, and I L-2, are copiously expressed in the microenvironment of the lymphoid t issues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observe d reappearance of detectable plasma viremia in HIV-infected individual s in whom HAART was discontinued. Moreover, since it is likely that th ese infected cells die upon activation of virus and that HAART prevent s spl-ead of virus to adjacent cells, the observation that this combin ation of cytokines can markedly induce viral replication in this reser voir may have important implications for the activation-mediated dimin ution of the latent reservoir of HIV in patients receiving HAART.