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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104483-01A1
Application #
8542053
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sanders, Brigitte E
Project Start
2013-07-17
Project End
2017-06-30
Budget Start
2013-07-17
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$360,725
Indirect Cost
$125,725
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Antonucci, Jenna M; St Gelais, Corine; de Silva, Suresh et al. (2016) SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nat Med 22:1072-1074
Tirumuru, Nagaraja; Zhao, Boxuan Simen; Lu, Wuxun et al. (2016) N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife 5:
St Gelais, Corine; Kim, Sun Hee; Ding, Lingmei et al. (2016) A Putative Cyclin-binding Motif in Human SAMHD1 Contributes to Protein Phosphorylation, Localization, and Stability. J Biol Chem 291:26332-26342
Ren, Xiao-Xin; Wang, Hai-Bo; Li, Chuan et al. (2016) HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA. J Biol Chem 291:4580-8
Bonifati, Serena; Daly, Michele B; St Gelais, Corine et al. (2016) SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology 495:92-100
Kodigepalli, Karthik M; Li, Minghua; Liu, Shan-Lu et al. (2016) Exogenous Expression of SAMHD1 Inhibits Proliferation and Induces Apoptosis in Cutaneous T-cell Lymphoma-derived HuT78 Cells. Cell Cycle :0
Wang, Feifei; St Gelais, Corine; de Silva, Suresh et al. (2016) Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection. Virology 487:273-84
Kohnken, Rebecca; Kodigepalli, Karthik M; Wu, Li (2015) Regulation of deoxynucleotide metabolism in cancer: novel mechanisms and therapeutic implications. Mol Cancer 14:176
Mates, Jessica M; de Silva, Suresh; Lustberg, Mark et al. (2015) A Novel Histone Deacetylase Inhibitor, AR-42, Reactivates HIV-1 from Chronically and Latently Infected CD4(+) T-cells. Retrovirology (Auckl) 7:1-5
St Gelais, Corine; Roger, Jonathan; Wu, Li (2015) Non-POU Domain-Containing Octamer-Binding Protein Negatively Regulates HIV-1 Infection in CD4(+) T Cells. AIDS Res Hum Retroviruses 31:806-16

Showing the most recent 10 out of 14 publications