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 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.
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.
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|Garforth, Scott J; Domaoal, Robert A; Lwatula, Chisanga et al. (2010) K65R and K65A substitutions in HIV-1 reverse transcriptase enhance polymerase fidelity by decreasing both dNTP misinsertion and mispaired primer extension efficiencies. J Mol Biol 401:33-44|
|Drosopoulos, William C; Prasad, Vinayaka R (2010) The telomerase-specific T motif is a restrictive determinant of repetitive reverse transcription by human telomerase. Mol Cell Biol 30:447-59|
|Garforth, Scott J; Parniak, Michael A; Prasad, Vinayaka R (2008) Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase. PLoS One 3:e2074|