Infection with HIV disproportionately affects drug dependent individuals. Furthermore, due to a variety of factors including comorbid conditions, decreased compliance, and increased development of resistance, the effectiveness of currently available HIV treatments is reduced in this population. The need for new ways of targeting HIV is therefore particularly acute in this population. However, despite the wealth of ongoing research in HIV drug development, most new drug candidates continue to target only a few well-defined protein domains, chosen for their functional importance in HIV replication. Targeting the RNA genome itself in a structure-directed manner presents an opportunity to greatly expand the repertoire of potential target sites for anti-HIV therapeutics. The long term goals of this project are to investigate new mechanisms of inhibiting HIV by targeting its RNA genome. To accomplish this, I will combine the unique structure-probing technologies developed in the sponsor laboratory with advances in the fields of antisense oligonucleotide inhibitor design and computational RNA structure determination to study novel ways of inhibiting HIV by directly targeting the genome using two different mechanisms. In addition to studying basic mechanisms of retroviral inhibition at the laboratory bench, I will also learn about the disease from a bedside perspective by spending 10% of my effort engaged in a unique clinical training and research experience with HIV patients in drug-abusing and prison populations.
My specific aims are to (1) inhibit HIV by inducing large-scale structural rearrangements in important regulatory domains in the HIV genome and (2) inhibit HIV reverse transcription by sterically blocking the enzyme using high-affinity antisense oligonucleotide analogs.

Public Health Relevance

The structure of the HIV RNA genome is crucial for the virus to replicate and infect human cells. My project will use detailed Information about HIV RNA structure to develop new ways of inhibiting the virus. The results of my work, when fully realized, will influence the development of new treatment options for people living with HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DA027364-03
Application #
8082788
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Avila, Albert
Project Start
2009-06-22
Project End
2014-06-21
Budget Start
2011-06-22
Budget End
2012-06-21
Support Year
3
Fiscal Year
2011
Total Cost
$29,815
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Low, Justin T; Garcia-Miranda, Pablo; Mouzakis, Kathryn D et al. (2014) Structure and dynamics of the HIV-1 frameshift element RNA. Biochemistry 53:4282-91
Low, Justin T; Knoepfel, Stefanie A; Watts, Joseph M et al. (2012) SHAPE-directed discovery of potent shRNA inhibitors of HIV-1. Mol Ther 20:820-8
Low, Justin T; Weeks, Kevin M (2010) SHAPE-directed RNA secondary structure prediction. Methods 52:150-8