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)
Project #
Application #
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
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
de Silva, Suresh; Wang, Feifei; Hake, Timothy S et al. (2014) Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sezary syndrome patients. J Invest Dermatol 134:562-5
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; 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
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; 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
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