Roughly 25% of HIV-infected persons who receive anti-retroviral therapy may experience a delayed and incomplete recovery of CD4+ T cells. These persons have been designated immune failures and are likely to have increased risk of complications. The proposed studies explore a potential mechanism of immune failure in HIV disease that centers on the immunoregulatory activities of type I interferon, an anti-viral innate defense molecule that is induced in HIV disease. We propose that type I interferon may act to suppress T cell proliferation and to promote T cell sequestration in lymph nodes during HIV infection and that these effects could contribute to poor immunologic recovery of T cells after initiation of therapy. We will focus our studies on understanding the potential for type I interfern to cause impairments in T cell responses to the homeostatic cytokine, interleukin-7 and to the lymph node egress mediator, S1P. By combining cell signaling analyses with transcriptomics, we will identify key molecular mediators of type I interferon activity and we will explore these effects in cells from HIV+ donors who have experienced immunologic failure while receiving anti-retroviral therapy. These studies will provide insight into mechanisms of immune failure in HIV disease and may uncover novel molecular pathways of type I interferon anti-proliferative and immunomodulatory effects.
Immune failure (poor CD4+ T cell recovery despite full virologic suppression) is not uncommon in HIV infected persons who are treated with combination anti-retroviral therapy. These studies investigate possible mechanisms to explain immune failure in HIV disease. The hypothesis states that an anti-viral molecule, type I interferon, is systemically increased in immune failure subjects, and that this cytokine interferes with the capacity of the immune system to reconstitute CD4+ T cells. In particular, we propose that the anti-proliferative activity of type I interferon, along with its potential to cause T cell sequestration in lymph nodes, could contribute to immune failure. If this hypothesis is correct, then neutralization of type I interferon might enhance T cell recovery in HIV infected patients who experience immune failure. Furthermore, by identifying the molecular mechanism of type I interferon activity, it may be possible to design interventions that circumvent the undesirable activities of type I interferon while preserving other innate immune functions of this cytokine.