# Blocking type I interferon signaling to reverse T cell exhaustion and control HIV-1 reservoirs > **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $833,168 ## Abstract 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). ## Key facts - **NIH application ID:** 10201432 - **Project number:** 5R01AI136990-05 - **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE - **Principal Investigator:** Rama Rao Amara - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $833,168 - **Award type:** 5 - **Project period:** 2018-07-01 → 2023-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10201432 ## Citation > US National Institutes of Health, RePORTER application 10201432, Blocking type I interferon signaling to reverse T cell exhaustion and control HIV-1 reservoirs (5R01AI136990-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201432. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*