Autoimmune Deficiency Syndrome (AIDS) is caused by the HIV retrovirus and is a deadly worldwide epidemic. One efficient strategy that viruses use is to hijack short functional motifs. These motifs are consensus sequences on different HIV proteins that are the binding sites or targets that host proteins act on to allow viral infection and replication. For example, the HIV envelope polyprotein (Env) contains a short consensus motif (Arg-x-Lys/Arg-Arg;""""""""x"""""""" is any residue) for cleavage by the host protease, Furin. One of the major limitations in identifying short functional motifs is the lack of a systematic approach and simple accessibility for HIV researchers. Our cross-disciplinary team has built Minimotif Miner (MnM), a motif database and platform-independent web-tool that identifies short motif consensus sequences (less that 15 residues) in protein queries and thus new potential functions in these proteins (http://mmm.engr.unconn.edu/). Many of these consensus sequences are present in HIV proteins. To facilitate the study of short functional motifs in HIV proteins, we proposed to provide a free new web system infrastructure that integrates information for protein motifs with sequence conservation among HIV isolates and 3D structures of HIV proteins to allow HIV researchers to explore new functions in HIV proteins. Short functional motifs provide a plethora of potential targets for intervention in the viral life-cycle that have not been thoroughly explored (Aims 1 and 2). A second goal of this proposal is to test some of the more exciting motif predictions. Consensus motifs in HIV proteins will be validated by mutating the motif in recombinant viruses, testing for the effect of the mutation on viral infection and replication, and then assaying the direct function of the predicted motif (e.g. interaction with another protein;
aim 3).

Public Health Relevance

This project provides a key tool to help understand the process by which HIV infects and replicates within cells. The proposed experiments are likely to identify new lead compounds for treating HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI078708-02
Application #
7632276
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Embry, Alan C
Project Start
2008-06-15
Project End
2009-07-31
Budget Start
2009-06-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$17,483
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Sargeant, David P; Deverasetty, Sandeep; Strong, Christy L et al. (2014) The HIVToolbox 2 web system integrates sequence, structure, function and mutation analysis. PLoS One 9:e98810
Sargeant, David P; Hedden, Michael W; Deverasetty, Sandeep et al. (2014) The Geogenomic Mutational Atlas of Pathogens (GoMAP) web system. PLoS One 9:e92877
Sargeant, David; Deverasetty, Sandeep; Luo, Yang et al. (2011) HIVToolbox, an integrated web application for investigating HIV. PLoS One 6:e20122
Vyas, Jay; Nowling, Ronald J; Meusburger, Thomas et al. (2010) MimoSA: a system for minimotif annotation. BMC Bioinformatics 11:328
Rajasekaran, Sanguthevar; Balla, Sudha; Gradie, Patrick et al. (2009) Minimotif miner 2nd release: a database and web system for motif search. Nucleic Acids Res 37:D185-90
Vyas, Jay; Gryk, Michael R; Schiller, Martin R (2009) VENN, a tool for titrating sequence conservation onto protein structures. Nucleic Acids Res 37:e124
Kadaveru, Krishna; Vyas, Jay; Schiller, Martin R (2008) Viral infection and human disease--insights from minimotifs. Front Biosci 13:6455-71