Monocytes are precursors of dendritic cells and macrophages, and these cell types play an important and multifaceted role in HIV-1 infection and pathogenesis. Undifferentiated primary monocytes are resistant to HIV-1 postentry infection, which is likely due to the expression of a potential restriction factor. A challenge in he field is to identify the host factor and understand its mechanisms underlying HIV-1 restriction of primary monocytes. In our preliminary study, we identified a cellular protein named UBE2V1 (ubiquitin-conjugating enzyme E2 variant 1) that can inhibit HIV-1 infection in monocytic cells. The goal of this R21 proposal is to explore the function and mechanisms of UBE2V1 in blocking HIV-1 infection in primary monocytes. We propose to test the hypothesis that post-translationally modified UBE2V1 inhibits HIV-1 replication in primary monocytes. The expected outcome of our proposed studies is to define a novel mechanism by which post-translational modifications of UBE2V1 regulate HIV-1 infection in monocyte-lineage cells. UBE2V1 (also called UEV1, UEV1A or CROC-1) belongs to the subfamily of ubiquitin-conjugating enzyme variant proteins and acts as a regulatory protein in DNA damage and cell differentiation. A recent study indicated that the retroviral restriction factor TRIM5 functions as an innate immune sensor for the retrovirus capsid lattice by interacting with the ubiquitin-conjugating enzyme complex UBC13-UBE2V1. This finding suggests that UBE2V1 is a novel component of the innate immune response. Interestingly, our preliminary studies indicate that post-translational modification of UBE2V1 is associated with HIV-1 restriction in primary monocytes. We propose to explore the role and mechanisms of UBE2V1 in HIV-1 restriction in primary monocytes in two specific aims.
Aim 1. Characterize UBE2V1-mediated restriction of the HIV-1 early lifecycle in primary monocytes.
Aim 2. Define the critical domains and residues of the modified UBE2V1 responsible for HIV-1 restriction in primary monocytes. The significant impact of our proposed studies will be to open a new area in the study of post- translational modifications of host factor involved in HIV-1 replication. We will define the molecular mechanism of HIV-1 restriction in monocyte-lineage cells by characterizing the function of UBE2V1 in HIV-1 infection. Accomplishing the proposed aims has the potential to advance basic knowledge of HIV-host interactions. Ultimately, the knowledge learned from the proposed studies will enable design of novel approaches to block HIV-1 replication in target cells.

Public Health Relevance

HIV-1 infection is a leading killer worldwide among infectious diseases, causing 2-3 million AIDS deaths annually. HIV-1 persistence is the major barrier to successful AIDS treatment. We propose to explore novel mechanisms by which a cellular protein named UBE2V1 restricts HIV- 1 replication in primary monocytes. The knowledge learned from the proposed studies will enable design of novel approaches to block HIV-1 persistent infection in target cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI098524-02
Application #
8418691
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2012-02-05
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$228,750
Indirect Cost
$78,750
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Wu, Li (2013) SAMHD1 knockout mice: modeling retrovirus restriction in vivo. Retrovirology 10:142
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Wu, Li (2013) Cellular and Biochemical Mechanisms of the Retroviral Restriction Factor SAMHD1. ISRN Biochem 2013:
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St Gelais, Corine; Coleman, Christopher M; Wang, Jian-Hua et al. (2012) HIV-1 Nef enhances dendritic cell-mediated viral transmission to CD4+ T cells and promotes T-cell activation. PLoS One 7:e34521
de Silva, Suresh; Planelles, Vicente; Wu, Li (2012) Differential effects of Vpr on single-cycle and spreading HIV-1 infections in CD4+ T-cells and dendritic cells. PLoS One 7:e35385
Coon, Sirena; Wang, Danxin; Wu, Li (2012) Polymorphisms of the SAMHD1 gene are not associated with the infection and natural control of HIV type 1 in Europeans and African-Americans. AIDS Res Hum Retroviruses 28:1565-73

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