PROJECT SUMMARY The long-term goal of this new project is to elucidate the mechanism of pDC/IFN-induced immune suppression during persistent HIV infection, and develop novel strategy of pDC/IFN-I blockade to control HIV reservoirs. I postulate that the HIV-activated pDC/IFN-I axis depletes and impairs anti-HIV T cells to maintain HIV- 1 persistence. Thus transient pDC/IFN-I interruption will provide a novel approach of immune recovery in cART- treated HIV-1 patients and improved control of viral rebound after cART cessation. In addition, restoring human immunity by transient pDC/IFN-I interruption prior to therapeutic vaccination will also enhance vaccine efficacy to control HIV-1 reservoirs. This project is proposed based on several recent findings from the multiple PIs’ labs in HIV-infected humanized mice and in SIV-infected NHP. (i) Although pDC/IFN-I is critical to suppress acute HIV-1 replication and to prime anti-HIV T cells, depletion of pDC during persistent HIV-1 infection reverses HIV-1 diseases in humanized mice, even in the presence of elevated HIV-1 replication, and rescued anti-HIV T cells. (ii) blocking IFNAR with an mAb also reversed HIV diseases in HIV infected humanized mice, “phenocopying” pDC depletion. (iii) In HIV-infected hu-mice under cART, IFNAR blockade or pDC depletion reversed inflammation, rescued human T cells and reduced HIV+ reservoir cells, via CD8-dependent mechanism. (iv) CD40-targeting vaccines induced T cell responses and reduced HIV reservoirs in humanized mice and SIV reservoirs in NHP. We hypothesize that IFN-I from persistently activated pDC contribute to HIV-induced aberrant inflammation, impaired immunity and HIV-1 persistence. The project will elucidate mechanisms of pDC/IFN-induced immune suppression (Aim 1) and functionally define the role of pDC/IFN-I in SIV persistence during cART (Aim 2). We will also explore the idea of blocking pDC/IFNAR prior to therapeutic vaccination under cART to control or cure HIV-1 or SIV reservoirs in humanized mice or in NHP models (Aim 3). Findings from the proposed aims will not only elucidate novel mechanisms of pDC/IFN-I in impairing host immunity, the IFNAR blocking bAb and pDC depleting dAb will also be developed into novel therapeutics to 1) resolve aberrant inflammation and recover immune activity in HIV- 1 patients under cART and 2) enhance therapeutic vaccination to achieve control of HIV rebound after cART interruption (functional cure).