The role of cytokines in the establishment, persistence and eradication of the HIV reservoir

Abstract

HIV persists in cellular and anatomical reservoirs during Highly Active Antiretroviral Therapy (HAART). In vitro studies as well as in vivo observations have identified cytokines as important factors regulating the immunological and virological mechanisms involved in HIV persistence. Immunosuppressive cytokines might contribute to the establishment of viral latency by dampening T cell activation and HIV production, thereby creating the necessary immuno-virological condition for the establishment of a pool of latently infected cells. Other cytokines that are involved in the maintenance of memory CD4(+) T cells promote the persistence of these cells during HAART. Conversely, proinflammatory cytokines may favor HIV persistence by exacerbating low levels of ongoing viral replication in lymphoid tissues even after prolonged therapy. The ability of several cytokines to interfere with the molecular mechanisms responsible for HIV latency makes them attractive candidates for therapeutic strategies aimed at reducing the pool of latently infected cells. In this article, we review the role of cytokines in HIV persistence during HAART and discuss their role as potential eradicating agents.

Fig. 1

Establishment of the latent viral reservoir. (A) Pre-activation establishment of the latent viral reservoir: Resting CD4⁺ T cells are exposed to HIV particles in a microenvironment enriched in γc cytokines and chemokines promoting the integration of provirus in the absence of cell activation. (B) Post-activation establishment of the latent viral reservoir: immunomodulatory cytokines (IL-10, TGF-β, IL-1RA) may down regulate activation of productively infected CD4⁺ T cells, thereby silencing viral transcription. γc cytokines promote the survival of latently infected cells. Altogether, this cytokinic environment may favor the establishment of long-lived latently infected CD4⁺ T cells.

Fig. 2

Role of cytokines in HIV persistence. IL-7 plays an important role in the homeostasis of CD4⁺ T cells and may ensure the long-term persistence of latently infected cells through homeostatic proliferation during HAART. Several cytokines expressed at high levels in the plasma and lymphoid tissues of HIV infected subjects such as TNF-α, IL-2, IL-12 and IL-18 may induce HIV reactivation from latently infected cells and sustain ongoing viral replication during HAART. As a potent pro-differentiation agent, IFN-γ may induce viral production in latently infected cells concomitant to cell-differentiation. In addition, by generating more targets for HIV infection, IFN-γ may in turn enhance viral replication.