This application is a revised proposal of a competing renewal that initially focused on identifying determinants and mechanisms by which HIV-1 Nef enhances viral infectivity. Published and preliminary data are presented to provide evidence that Nef contains sorting motifs that dysregulate cellular protein sorting. It is hypothesized that this effect underlies Nef's varied functions including the ability to downregulate CD4 and HLA class-I molecules and to enhance viral infectivity and replication. The primary goal of the proposal is to identify and characterize these motifs, elucidate the interactions that they mediate, and determine the biological consequences of these effects. The initial application was criticized largely on the grounds that alternative approaches and confounding variables had not been considered, that potentially interesting differences in SIV Nef had not been incorporated into the hypothesis, and that the proposal suffered at times from an overall lack of clarity. The PI has responded to these criticisms with an extensively rewritten proposal that incorporates several new (albeit risky) approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI038201-04A1
Application #
6020253
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Sarver, Nava
Project Start
1996-08-15
Project End
2003-07-31
Budget Start
1999-08-15
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Sherrill-Mix, Scott; Lewinski, Mary K; Famiglietti, Marylinda et al. (2013) HIV latency and integration site placement in five cell-based models. Retrovirology 10:90
Jia, Xiaofei; Singh, Rajendra; Homann, Stefanie et al. (2012) Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef. Nat Struct Mol Biol 19:701-6
Tokarev, Andrey; Guatelli, John (2011) Misdirection of membrane trafficking by HIV-1 Vpu and Nef: Keys to viral virulence and persistence. Cell Logist 1:90-102
Homann, Stefanie; Smith, Davey; Little, Susan et al. (2011) Upregulation of BST-2/Tetherin by HIV infection in vivo. J Virol 85:10659-68
Fitzpatrick, Kathleen; Skasko, Mark; Deerinck, Thomas J et al. (2010) Direct restriction of virus release and incorporation of the interferon-induced protein BST-2 into HIV-1 particles. PLoS Pathog 6:e1000701
Mitchell, Richard S; Katsura, Chris; Skasko, Mark A et al. (2009) Vpu antagonizes BST-2-mediated restriction of HIV-1 release via beta-TrCP and endo-lysosomal trafficking. PLoS Pathog 5:e1000450
Day, John R (2009) CCD camera detection of HIV infection. Methods Mol Biol 503:203-19
Guatelli, John C (2009) Interactions of viral protein U (Vpu) with cellular factors. Curr Top Microbiol Immunol 339:27-45
Van Damme, Nanette; Goff, Daniel; Katsura, Chris et al. (2008) The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3:245-52
Dueck, Megan; Guatelli, John (2007) Evidence against a direct antiviral activity of the proteasome during the early steps of HIV-1 replication. Virology 361:1-8