The purpose of the proposed studies is to understand the HIV-1 frameshift (FS) mechanism and to learn how it can be targeted with small, drug-like molecules. The HIV-1 FS site is a highly conserved genomic RNA structure located between the gag and pol reading frames. Its purpose is to stimulate a -1 FS that is required for expression of the Pol genes, which are in the -1 reading frame relative to Gag. We have solved the structure of the HIV-1 FS RNA, both alone and in complex with small drug-like molecules. We will use high throughput screens to identify small molecules that bind to and modulate the HIV-1 FS RNA, both in vitro and in vivo. The best small molecule ligands will be identified as lead compounds. The structures of the HIV-1 FS RNA in complex with lead compounds will be solved, in order to understand the basis for their modes of action. From this information, novel second generation compounds will be developed with improved affinity, specificity and potency. Additionally, we will investigate the FS mechanism, which is currently not well understood. Elucidation of the FS mechanism will provide a better understanding of this essential feature of the viral life cycle, which is utilized by all retroviruses. Finally, we will investigate the structure and function of the entire HIV-1 genomic FS domain, which has been recently identified and is hypothesized to function in slowing the kinetics of translation prior to the FS.

Public Health Relevance

More than 30 million people are infected with Human immunodeficiency virus (HIV), the causative agent of AIDS. Results of the proposed studies will elucidate how HIV stimulates translational frameshifting, a critical step in the viral replication cycle. Small drug-like molecules that inhibit viral replication by targeting this mechanism will be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072447-07
Application #
8249837
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Preusch, Peter C
Project Start
2005-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
7
Fiscal Year
2012
Total Cost
$279,378
Indirect Cost
$87,228
Name
University of Wisconsin Madison
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Mouzakis, Kathryn D; Lang, Andrew L; Vander Meulen, Kirk A et al. (2013) HIV-1 frameshift efficiency is primarily determined by the stability of base pairs positioned at the mRNA entrance channel of the ribosome. Nucleic Acids Res 41:1901-13
Wang, Xiao-Ming; Yik, Wing Yan; Zhang, Peilin et al. (2012) The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis. Stem Cell Res Ther 3:39

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