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
Buzovetsky, Olga; Tang, Chenxiang; Knecht, Kirsten M et al. (2018) The SAM domain of mouse SAMHD1 is critical for its activation and regulation. Nat Commun 9:411
Chen, Shuliang; Bonifati, Serena; Qin, Zhihua et al. (2018) SAMHD1 Suppression of Antiviral Immune Responses. Trends Microbiol :
Guo, Jing; Liu, Xianxian; Wu, Chuanjian et al. (2018) The transmembrane nucleoporin Pom121 ensures efficient HIV-1 pre-integration complex nuclear import. Virology 521:169-174
Chen, Shuliang; Bonifati, Serena; Qin, Zhihua et al. (2018) SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-?B and interferon pathways. Proc Natl Acad Sci U S A 115:E3798-E3807
St Gelais, Corine; Kim, Sun Hee; Maksimova, Victoria V et al. (2018) A Cyclin-Binding Motif in Human SAMHD1 Is Required for Its HIV-1 Restriction, dNTPase Activity, Tetramer Formation, and Efficient Phosphorylation. J Virol 92:
Kodigepalli, Karthik M; Bonifati, Serena; Tirumuru, Nagaraja et al. (2018) SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis. Cell Cycle 17:1124-1137
Antonucci, Jenna M; Kim, Sun Hee; St Gelais, Corine et al. (2018) SAMHD1 Impairs HIV-1 Gene Expression and Negatively Modulates Reactivation of Viral Latency in CD4+ T Cells. J Virol 92:
Kodigepalli, Karthik M; Li, Minghua; Liu, Shan-Lu et al. (2017) Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle 16:179-188
Kohnken, Rebecca; Kodigepalli, Karthik M; Mishra, Anjali et al. (2017) MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells derived from S├Ęzary syndrome patients. Leuk Res 52:58-66
Wang, Qiankun; Chen, Shuliang; Xiao, Qiaoqiao et al. (2017) Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection. Retrovirology 14:51

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