Non-venous-injected HIV infection is thought to occur at mucosal surfaces where epithelial cells serve as the primary conduit to secondary infection of macrophages. These macrophages then repackage virus for infection of T-cells but as importantly they act as long-term reservoirs of virus even in AIDS patients with well-controlled disease. Understanding the biology of HIV infected macrophages is thus a central part of designing strategies to control and eliminate the virus. Several therapeutics are now combined and are in clinical use (HAART). These block viral protease and reverse trascriptase activities but additional drugs are essential.
Our aim i s to validate another HIV therapeutic target ie. the transcription of the virus genome, and our ultimate goal is to design agents that will block this process. HIV transcription is driven by the long terminal repeat (LTR) but maximal elongation is dependent upon HIV-encoded-Tat binding to a viral RNA stem loop, TAR. HIV infection is substantially improved when cells express high levels of a hematopoetic transcription factor, c-MYB. There are 15 potential c-MYB binding sites within the HIV-LTR; one highly conserved site in most HIV subtypes is essential to c-MYB activation of the LTR. Exogenous c-MYB leads to increased reverse transcriptase activity and virus production. The c-MYB gene contains an intronic regulatory sequence that blocks elongation in most non-hematopoietic cells. Tat reverses this block allowing elevated c-MYB that is biologically advantageous to HIV. Therefore we propose that HIV has evolved a mechanism to activate a cellular gene that is central to the transcription of its own genome. We hypothesize that Tat activates c-MYB in macrophages and that a thorough understanding of this process will advance our goal of blocking HIV transcription.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI054158-01A1
Application #
6696051
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Young, Janet M
Project Start
2003-08-15
Project End
2005-07-31
Budget Start
2003-08-15
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$150,000
Indirect Cost
Name
Peter Maccallum Cancer Centre
Department
Type
DUNS #
City
East Melbourne
State
Country
Australia
Zip Code
3172
Pereira, Lloyd A; Hugo, Honor J; Malaterre, Jordane et al. (2015) MYB elongation is regulated by the nucleic acid binding of NF?B p50 to the intronic stem-loop region. PLoS One 10:e0122919