The experiments proposed here focus on testing our hypothesis that HIV-1 Tat and Vpr may stimulate dNTP biosynthesis by hijacking cellular pathways for efficient HIV-1 replication in terminally-differentiated host cells (macrophage and microglia). HIV-1 Tat may promote dNTP biosynthesis through the activation of survival and proliferation pathways, promoting entry into S phase and thus activation of genes associated with dNTP biosynthesis. Vpr, however, triggers the activation of the DNA damage pathway, which likely also enhances dNTP, enhancing DNA gap repair. Studies providing insight into Vpr's effect will examine the potential effect of different sources of Vpr, notably (i) cell-free (non-virion) Vpr, (ii) virion-associated Vpr and (iii) newly synthesized Vpr on the DNA gap-repair step that is essential for proviral DNA integration. Experiments addressing the mechanism of dNTP biosynthesis by expression of HIV-1 Tat will provide insight into the long-term survival of viral reservoirs such as macrophage and may explain their susceptibility to superinfection, thus increasing viral diversity. If specific cellular components involved in the effects elicited by Vpr or Tat (e.g. Akt, CHK1) are identified, then these studies may suggest possible new antiviral targets. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI064136-01A1
Application #
7150785
Study Section
Special Emphasis Panel (ZRG1-IMM-L (29))
Program Officer
Hernandez, Milton J
Project Start
2006-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$45,235
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Chugh, Pauline; Bradel-Tretheway, Birgit; Monteiro-Filho, Carlos M R et al. (2008) Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology 5:11
Chugh, Pauline; Fan, Shongshan; Planelles, Vicente et al. (2007) Infection of human immunodeficiency virus and intracellular viral Tat protein exert a pro-survival effect in a human microglial cell line. J Mol Biol 366:67-81