In the next 5-year phase of this R37 grant, we will continue our investigations in 2 of the three aims originally proposed.
The third Aim, is a new aim and outgrowth of the current trends In HIV research of Investigating the role of host factors in specific viral functions.
In Aim 1, we will continue the wori In Aim 2, we will continue our previous work on RT-IN complexes by co-crystallizing HIV-1 RT-IN complexes in collaboration with Dr. Steve Almo. When the structural information becomes available, we can carry out site-directed mutagenesis to disrupt residues in the interaction interface and carry out genetic protein-protein interaction assays and virological assays to determine the significance of the interaction.
In Aim 3, we will Investigate the role of host factors in HIV reverse transcription. We will examine the genes Implicated in reverse trancription by shRNA screens by Konig et al. The specific role of selected genes in reverse transcription will be confirmed by eliminating possible effects on entry and/or uncoating. First, we will develop an interactome of each hit via co-1.P. from both infected and uninfected cells to understand the pathways involved. Second, we will silence other members of the complexes thus identified for role in reverse transcription. Third, we will test whether the silencing of the 'hit's or their interacting partners will affect only HIV or also the related lenti- and retroviruses including SIVcpz, SIVmac, HIV-2, MuLV and RSV - to understand the wider significance of the proteins thus identified to retroviruses.

Public Health Relevance

We believe that the proposed work can lead to the development of analogs of dNTP that can either enhance fidelity or push the error rate above the error catastrophe - both of which affect virus fitness and thus should be potent means of virus suppression. Delineation of interaction between RT and IN will allow the development of reagents to block this essential interaction. Delineation of host factors specifically involved in reverse transcription will help evolve a new class of drugs that targeting host proteins.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Ussery, Michael A
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Albert Einstein College of Medicine
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