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Retroviral Replication and Interactions with Host Factors

Vinay Pathak

1 Collaborator(s)

Funding source

National Cancer Institute (NIH)
We are carrying out live-cell microscopy to examine the movement of HIV-1 complexes in infected cells, determine the kinetics of their association with the NE, and visualize their nuclear import. We will determine whether interactions between HIV-1 integrase and host proteins LEDGF and/or HRP-2 are critical for the tethering of HIV-1 PICs to the chromatin domains near the NE. We will develop methods to visualize integrated proviral DNAs and compare the distribution of PICs to proviral DNAs in infected cells. Wild-type HIV-1 can infect non-dividing cells, but some HIV-1 CA mutants and MLV can only infect dividing cells. We will analyze NE association and nuclear import of these HIV-1 mutants and MLV to determine the stage at which infection of non-dividing cells is blocked. HIV-1 viral cores are disassembled after infection in a poorly understood process known as uncoating. We will analyze the kinetics and nature of HIV-1 uncoating in infected cells by labeling viral complexes with A3F-YFP and other fluorescent markers. Host protein cyclophilin binds to HIV-1 CA in infected cells, but the functional consequences of this interaction on viral replication are not well understood. We are examining the impact of cyclophilin-binding CA mutants to NE association and nuclear import to elucidate this virus-host interaction. MX2 is a recently identified host restriction factor that inhibits HIV-1 replication by binding to viral cores. We are analyzing replication of A3F-YFP-labeled virions in MX2-expressing cells to determine the mechanism(s) by which MX2 inhibits HIV-1 replication. _____[Corresponds to Pathak Project 3 in the October 2011 site visit report of the HIV Drug Resistance Program]

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