- This research plan addresses two issues relating to coreceptor use by the HIV envelope glycoprotein gp120. The first is the selective pressures that favor transmission of CCR5-using (R5) HIV-1 at the time of primary infection. These studies are important for defining the selection pressures surrounding transmission and are of great importance for vaccine development and the potential use of CCR5 inhibitors in microbicides. We will characterize a series of primary transmission envelope clones, and then use them to test two hypotheses: (1) that transmitted virus is more stable under the physiological conditions of transmission, and (2) that selective infection of myeloid dendritic cells favors R5 virus transmission. The second issue addresses the selective forces that allow emergence of CXCR4-using viruses in 50% of patients after prolonged infection. We will characterize a longitudinal series of envelopes from early to end- stage infection and use them to test four additional hypotheses: (1) that the probability of coreceptor switching is influenced by the way in which envelope evolves to engage different extracellular domains of CCR5;(2) that CXCR4-using variants (R5X4 or X4 viruses) only emerge when antibody responses to envelope disappear;(3), that evolution of R5 viruses reaches a fitness ceiling in some patients that is followed by an abrupt loss of fitness that allows X4 viral variants to emerge without competition;and (4), that binding to sulfated glycosaminoglycans promotes coreceptor switching. The envelope sequences responsible for these functional changes will be mapped. These experiments are highly relevant to the approaching use of CCR5 inhibitors in phase III clinical trials, and may well predict the probability of resistance to this class of antivirals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052778-07
Application #
7624263
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Salzwedel, Karl D
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
7
Fiscal Year
2009
Total Cost
$451,272
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Dobrowsky, Terrence M; Rabi, S Alireza; Nedellec, Rebecca et al. (2013) Adhesion and fusion efficiencies of human immunodeficiency virus type 1 (HIV-1) surface proteins. Sci Rep 3:3014
Choi, Won-Tak; Nedellec, Rebecca; Coetzer, Mia et al. (2012) CCR5 mutations distinguish N-terminal modifications of RANTES (CCL5) with agonist versus antagonist activity. J Virol 86:10218-20
Nedellec, Rebecca; Coetzer, Mia; Lederman, Michael M et al. (2011) Resistance to the CCR5 inhibitor 5P12-RANTES requires a difficult evolution from CCR5 to CXCR4 coreceptor use. PLoS One 6:e22020
Coetzer, Mia; Nedellec, Rebecca; Cilliers, Tonie et al. (2011) Extreme genetic divergence is required for coreceptor switching in HIV-1 subtype C. J Acquir Immune Defic Syndr 56:9-15
da Silva, Jack; Coetzer, Mia; Nedellec, Rebecca et al. (2010) Fitness epistasis and constraints on adaptation in a human immunodeficiency virus type 1 protein region. Genetics 185:293-303
Nedellec, Rebecca; Coetzer, Mia; Lederman, Michael M et al. (2010) ""Resistance"" to PSC-RANTES revisited: two mutations in human immunodeficiency virus type 1 HIV-1 SF162 or simian-human immunodeficiency virus SHIV SF162-p3 do not confer resistance. J Virol 84:5842-5
Mosier, Donald E (2009) How HIV changes its tropism: evolution and adaptation? Curr Opin HIV AIDS 4:125-30
Nedellec, R; Coetzer, M; Shimizu, N et al. (2009) Virus entry via the alternative coreceptors CCR3 and FPRL1 differs by human immunodeficiency virus type 1 subtype. J Virol 83:8353-63
Coetzer, Mia; Nedellec, Rebecca; Salkowitz, Janelle et al. (2008) Evolution of CCR5 use before and during coreceptor switching. J Virol 82:11758-66
Kiselyeva, Yana; Nedellec, Rebecca; Ramos, Alejandra et al. (2007) Evolution of CXCR4-using human immunodeficiency virus type 1 SF162 is associated with two unique envelope mutations. J Virol 81:3657-61

Showing the most recent 10 out of 15 publications