EXCEED THE SPACE PROVIDED. 'Coreceptor switching' is the evolution of the HIV-1 envelope from exclusive use of CCR5 for viral entry to alternative use of CCR5 or CXCR4 and finally to exclusive use of CXCR4. Viruses that can use CXCR4 as a coreceptor have an expanded target cell range and cause more rapid disease progression. Coreceptor switching occurs at different rates in different patients, and may not occur at all. The potential use of CCR5 inhibitors for antiviral therapy may substantially increase the rate of coreceptor switching. The goal of this proposal is to define the viral and host determinants that influence the rate of coreceptor switching. Viral determinants of coreceptor switching to be investigated include relative avidity for CCR5, fitness of 'transitional state' viruses undergoing coreceptor change, binding to CXCR4 without functional use of the coreceptor, and efficiency of clade C versus clade B viruses viruses in coreceptor switching assays in vitro and in hu-PBL-SCID mice. Host factors to be investigated include CCR2, CCR5, and IL-4 promoter polymorphisms, relative numbers of Thl versus Th2 CD4 T cells, IL-4 and IL-12 cytokine levels, and relative numbers of memory effector versus central memory CD4 T cells. The information gained will be important for understanding disease progression and the safety of coreceptor inhibitors. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052778-03
Application #
6840421
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (11))
Program Officer
Wassef, Nabila M
Project Start
2002-12-06
Project End
2006-05-31
Budget Start
2004-12-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$422,325
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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

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