The goal of this research project is to identify and characterize genetic polymorphisms within the regulatory regions of the CCR5 and CXCR4 co-receptors for HIV-1 entry, and to determine their influences on the efficiency of HIV-1 transmission and the rate of disease progression in infected individuals. We have shown that CCR5 expression is highly variable on CD4+ T cells from individuals with wild-type CCR5 protein coding alleles. We have identified polymorphisms in the twin promoters for CCR5 and have shown that some of these are associated with reduced CCR5 protein expression and delayed disease progression. We have also found that a polymorphism in the CCR2 chemokine receptor (V641) that is associated with delayed disease progression is 100% genetically linked to a polymorphism in he region containing the CCR5 promoter. There are also partial linkages between CCR5 promoter polymorphisms and the CCR5-32 allele. Our first Specific Aim involves characterizing genetic polymorphisms within the CCR5 and CXCR4 regulatory regions, including their effects on 'transcription efficiency, cell surface protein expression and susceptibility of the target cells to HIV-1 infection. In the second Specific Aim, we will measure the frequencies of CCR5 and CXCR4 promoter polymorphisms (and of the CCR5-32 and CCR2-64I alleles) in AIDS- related cohorts., and determine their association with HIV-1 transmission and disease progression.
In Specific Aim 3, we will study the mechanisms by which CCR5 and CXCR4 gene expression is up- and down-regulated in response to different external stimuli and in different cells, and how this is influence by chemokines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043868-03
Application #
6170809
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Plaeger, Susan F
Project Start
1998-09-15
Project End
2001-06-30
Budget Start
2000-09-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$277,529
Indirect Cost
Name
Aaron Diamond AIDS Research Center
Department
Type
DUNS #
786658872
City
New York
State
NY
Country
United States
Zip Code
10016
Metzner, Karin J; Binley, James M; Gettie, Agegnehu et al. (2006) Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques. Retrovirology 3:97
Petridou, Eleni; Klimentopoulou, Alexandra E; Moustaki, Maria et al. (2002) Recent thymic emigrants and prognosis in T- and B-cell childhood hematopoietic malignancies. Int J Cancer 101:74-7
Gao, F; Vidal, N; Li, Y et al. (2001) Evidence of two distinct subsubtypes within the HIV-1 subtype A radiation. AIDS Res Hum Retroviruses 17:675-88
John, G C; Bird, T; Overbaugh, J et al. (2001) CCR5 promoter polymorphisms in a Kenyan perinatal human immunodeficiency virus type 1 cohort: association with increased 2-year maternal mortality. J Infect Dis 184:89-92
Goedert, J J; O'Brien, T R; Hatzakis, A et al. (2001) T cell receptor excision circles and HIV-1 2-LTR episomal DNA to predict AIDS in patients not receiving effective therapy. AIDS 15:2245-50
Paraskevis, D; Magiorkinis, M; Vandamme, A M et al. (2001) Re-analysis of human immunodeficiency virus type 1 isolates from Cyprus and Greece, initially designated 'subtype I', reveals a unique complex A/G/H/K/? mosaic pattern. J Gen Virol 82:575-80
Maayan, S; Zhang, L; Shinar, E et al. (2000) Evidence for recent selection of the CCR5-delta 32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews. Genes Immun 1:358-61
Metzner, K J; Jin, X; Lee, F V et al. (2000) Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Exp Med 191:1921-31
Martinson, J J; Hong, L; Karanicolas, R et al. (2000) Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype. AIDS 14:483-9
Kostrikis, L G (2000) Impact of natural chemokine receptor polymorphisms on perinatal transmission of human immunodeficiency virus type 1. Teratology 61:387-90

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