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.
|Duclair, Sonald; Gautam, Archana; Ellington, Andrew et al. (2015) High-affinity RNA Aptamers Against the HIV-1 Protease Inhibit Both In Vitro Protease Activity and Late Events of Viral Replication. Mol Ther Nucleic Acids 4:e228|
|Garforth, Scott J; Lwatula, Chisanga; Prasad, Vinayaka R (2014) The lysine 65 residue in HIV-1 reverse transcriptase function and in nucleoside analog drug resistance. Viruses 6:4080-94|
|Prasad, Vinayaka R; Bukrinsky, Michael I (2014) New clues to understanding HIV nonprogressors: low cholesterol blocks HIV trans infection. MBio 5:e01396-14|
|Rao, Vasudev R; Neogi, Ujjwal; Eugenin, Eliseo et al. (2014) The gp120 protein is a second determinant of decreased neurovirulence of Indian HIV-1C isolates compared to southern African HIV-1C isolates. PLoS One 9:e107074|
|Neogi, Ujjwal; Rao, Shwetha D; Bontell, Irene et al. (2014) Novel tetra-peptide insertion in Gag-p6 ALIX-binding motif in HIV-1 subtype C associated with protease inhibitor failure in Indian patients. AIDS 28:2319-22|
|Hanna, Luke Elizabeth; Neogi, Ujjwal; Ranga, Udaykumar et al. (2014) Phylogenetic characterization of six full-length HIV-1 subtype C molecular clones from three patients: identification of rare subtype C strains containing two NF-ÎºB motifs in the long terminal repeat. AIDS Res Hum Retroviruses 30:586-91|
|Mathew, Sheeba; Nguyen, Minh; Wu, Xuhong et al. (2013) INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo. Retrovirology 10:66|
|Kim, Jiae; Wang, Ligong; Li, Yongfeng et al. (2012) Pre-steady state kinetic analysis of cyclobutyl derivatives of 2'-deoxyadenosine 5'-triphosphate as inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 22:4064-7|
|Neogi, Ujjwal; Gupta, Soham; Sahoo, Pravat Nalini et al. (2012) Genetic characterization of HIV type 1 Tat exon 1 from a southern Indian clinical cohort: identification of unique epidemiological signature residues. AIDS Res Hum Retroviruses 28:1152-6|
|Lwatula, Chisanga; Garforth, Scott J; Prasad, Vinayaka R (2012) Lys66 residue as a determinant of high mismatch extension and misinsertion rates of HIV-1 reverse transcriptase. FEBS J 279:4010-24|
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