The HIV-1 pre-integration complex (PIC) that comprises of HIV-1 full-length DNA, viral proteins, and host proteins is essential for viral integration and replication. Previous studies have identified and characterized several human proteins that interact with HIV-1 integrase and play important roles in viral infection. However, the technical limitations in acquiring sufficient amounts of catalytically active PICs has hindered a comprehensive identification of host proteins associated with the HIV-1 PICs. We recently developed a novel approach and identified 18 new human proteins that are specifically associated with the HIV-1 PICs isolated from infected CD4+ T cells. Our preliminary study suggested that one of these proteins, non-POU domain-containing octamer-binding protein (NonO), is required for efficient HIV-1 infection in CD4+ T cells. However, it is unclear whether the other 17 PIC- associated host proteins that we identified can affect HIV-1 infection. NonO is a multifunctional nuclear protein involved in transcription regulation, mRNA splicing, and DNA repair in the cell, but the mechanism by which NonO affects HIV-1 infection is not known. We seek to address these two significant questions in this R21 proposal. We hypothesize that host proteins (such as NonO) specifically associated with catalytically active PICs in HIV-1-infected cells play a role in viral integration and infection. The following two specific aims are designed o test this hypothesis:
Aim 1. To determine the role of novel PIC-associated host proteins in HIV-1 infection. In addition to NonO, we may identify other PIC-associated host proteins among these 18 candidates that can significantly affect HIV-1 infection in Aim 1. We will select 2-3 protein candidates that have the most significant effect on viral infection to further study their mechanisms of action.
Aim 2. To investigate the mechanisms by which PIC-associated host proteins affect HIV-1 infection. We will first investigate the mechanism by which NonO affects HIV-1 infection, and we will then perform similar studies to examine other protein candidates identified in Aim 1. The long-term goal of this project is to understand the function and mechanism of PIC-associated host proteins in HIV-1 integration or infection and to develop novel therapeutic strategies. An emerging anti-HIV therapeutic strategy is to block the interactions between HIV-1 integrase and its critical cellular cofactors. Our proposed study has the potential to identify novel drug targets to block HIV-1 integration and infection.

Public Health Relevance

There are over 33 million people living with HIV worldwide and approximately 56,300 new HIV infections each year in the US. Although antiretroviral therapy can control HIV-1 infection in infected individuals, new anti-HIV drug targets are needed to increase efficacy and prevent drug resistance. This project aims to identify and characterize novel host proteins that are essential for the HIV integration process. The findings from the proposed studies will help identify novel drug targets for blocking HIV integration and infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI102822-01
Application #
8410611
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2012-07-20
Project End
2014-06-30
Budget Start
2012-07-20
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$190,625
Indirect Cost
$65,625
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
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
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
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
Wu, Li (2013) Cellular and Biochemical Mechanisms of the Retroviral Restriction Factor SAMHD1. ISRN Biochem 2013:
Wu, Li (2012) SAMHD1: a new contributor to HIV-1 restriction in resting CD4+ T-cells. Retrovirology 9:88
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

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