TNPO3 is a cellular nuclear import receptor required for HIV-1 infection. Depletion of TNPO3 expression dramatically decreases the infection of primate lentiviruses such as HIV-1, HIV-2 and SIVmac. TNPO3 is essential for early steps on HIV-1 replication. The viral determinant for the requirement of TNPO3 in HIV-1 infection has been genetically mapped to the viral capsid. In agreement with these observations, we have demonstrated that TNPO3 specifically binds the HIV-1 core that is composed of capsid. These results imply that TNPO3 might be interacting with the incoming HIV-1 core early on infection. Depletion of TNPO3 moderately but consistently affects the uncoating process of HIV-1. It is believed that TNPO3 is involved in the nuclear import of the HIV-1 pre-integration complex (PIC);however, this interpretation is in question, as more recent evidence implies that TNPO3 assists HIV-1 replication after nuclear import. Considering the following evidence: 1) depletion of TNPO3 expression affects HIV-1 replication, 2) the viral determinant for the requirement of TNPO3 maps to capsid, 3) TNPO3 binds the HIV-1 capsid, 4) depletion of TNPO3 expression moderately but consistently affects uncoating, and 5) our recent observation that TNPO3 assists HIV-1 replication in an step after nuclear import but before integration. We will test the hypothesis that the binding of TNPO3 to the HIV-1 core in the cytoplasm allows the occurrence of a process that is required for productive infection when the pre-integration complex reaches the nucleus. This proposal will explore the contribution of TNPO3 to HIV-1 integration into the genome by monitoring the two pivotal processes mediated by HIV-1 integrase in the absence of TNPO3, namely 3'-prime processing and DNA strand transfer. Secondly, we will study the role of TNPO3 nuclear-import in HIV-1 infection. The goal of these studies are to understand the mechanism used by TNPO3 to assist HIV-1 replication with the future objective of using TNPO3 as a therapeutic target to block HIV-1 replication. !

Public Health Relevance

TNPO3 is a nuclear import receptor essential for HIV-1 replication in human cells. This work will attempt to uncover the molecular mechanism used by TNPO3 to assist HIV-1 replication. Understanding the role of TNPO3 in HIV-1 infection will create opportunities for the development of novel therapies against HIV-1/AIDS. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI102824-01A1
Application #
8467375
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$235,470
Indirect Cost
$94,470
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
White, Tommy E; Brandariz-Nuñez, Alberto; Valle-Casuso, Jose Carlos et al. (2014) Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility. Virology 460-461:34-44
Fricke, Thomas; White, Tommy E; Schulte, Bianca et al. (2014) MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology 11:68