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.

Public Health Relevance

HIV-1 infection is a leading killer worldwide among infectious diseases, causing 2-3 million AIDS deaths annually. We propose to investigate the mechanism of a cellular protein named SAMHD1 inhibiting HIV-1 infection in human dendritic cells. The proposed studies will generate important new information to better understand how certain types of immune cells protect themselves from HIV-1 infection, which may help design more effective strategies to control HIV/AIDS.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sanders, Brigitte E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
Sharma, Amit; Slaughter, Alison; Jena, Nivedita et al. (2014) A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog 10:e1004171
St Gelais, Corine; de Silva, Suresh; Hach, Jocelyn C et al. (2014) Identification of cellular proteins interacting with the retroviral restriction factor SAMHD1. J Virol 88:5834-44