Immune activation is the driving force of HIV-1 replication in vivo, which facilitates viral infection in target cells and fundamentally contribute to AIDS pathogenesis. Myeloid cells, including monocytes, dendritic cells (DCs) and macrophages, play a critical role in innate immunity against viral infection. Our long-term goal is to define th mechanisms regulating immune activation of myeloid cells during HIV-1 infection. SAMHD1 is a recently identified HIV-1 restriction factor in myeloid cells. SAMHD1 a nuclear protein involved in innate immunity and has been proposed to act as a negative regulator of the interferon response. However, the role of SAMHD1 in regulating immune activation of myeloid cells remains unknown. The molecular mechanisms of SAMHD1-mediated HIV-1 restriction in DCs are not fully understood. In this project, we aim to study the mechanisms of SAMHD1-mediated HIV-1 restriction in primary DCs and the role of SAMHD1 in regulating immune activation of DCs. In our preliminary studies, we observed that HIV-1 infection of DCs significantly up-regulated the release of some early pro-inflammatory cytokines. Intriguingly, we found that HIV-1 infection of DCs resulted in the translocation of SAMHD1 from the nucleus to the cytoplasm. Our central hypotheses are: HIV-1 infection of DCs triggers SAMHD1 cytoplasmic translocation, which is important for HIV-1 restriction and immune suppression of DCs. As a result, HIV-1 restriction by SAMHD1 in DCs negatively regulates DC-mediated activation of CD4+ T-cells and HIV-1 transmission, which sets up a less permissive environment for HIV-1 spreading. We propose two specific aims to test these novel hypotheses. Aim 1. To examine the role of SAMHD1 in suppression of immune activation of DCs during HIV-1 infection; and Aim 2. To define the mechanisms of SAMHD1-mediated HIV-1 restriction in DCs. Our proposed studies will reveal the unique role of SAMHD1 in regulating immune activation of myeloid DCs during HIV-1 infection and define the precise mechanisms of SAMHD1-mediated HIV-1 restriction in primary DCs. Accomplishing the proposed studies will also elucidate the mechanisms by which SAMHD1 negatively regulates DC-mediated HIV-1 trans-infection and activation of CD4+ T-cells. Overall, our results will provide new insights into intrinsic immunity against HIV-1 infectin in myeloid DCs, which can help us to develop novel interventions to block HIV-1 infection and transmission.
NIH ExPorter
NIH ExPorter