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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sharma, Opendra K
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Ohio State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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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
de Silva, Suresh; Wang, Feifei; Hake, Timothy S et al. (2014) Downregulation of SAMHD1 expression correlates with promoter DNA methylation in S├ęzary syndrome patients. J Invest Dermatol 134:562-565
Wu, Li (2013) SAMHD1 knockout mice: modeling retrovirus restriction in vivo. Retrovirology 10:142
de Silva, Suresh; Hoy, Heather; Hake, Timothy S et al. (2013) Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells. J Biol Chem 288:9284-92
Wu, Li (2013) Cellular and Biochemical Mechanisms of the Retroviral Restriction Factor SAMHD1. ISRN Biochem 2013:
Coleman, Christopher M; Gelais, Corine St; Wu, Li (2013) Cellular and viral mechanisms of HIV-1 transmission mediated by dendritic cells. Adv Exp Med Biol 762:109-30
Dong, Chunsheng; Zhao, Guoping; Zhong, Mei et al. (2013) RNA sequencing and transcriptomal analysis of human monocyte to macrophage differentiation. Gene 519:279-87
St Gelais, Corine; de Silva, Suresh; Amie, Sarah M et al. (2012) SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+ T-lymphocytes cannot be upregulated by interferons. Retrovirology 9:105
Zhang, Chiyu; de Silva, Suresh; Wang, Jian-Hua et al. (2012) Co-evolution of primate SAMHD1 and lentivirus Vpx leads to the loss of the vpx gene in HIV-1 ancestor. PLoS One 7:e37477
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

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