title: Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.
abstract: Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, Audie L. Murphy Division, 78284-7870, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mummidi
authors.forename: S S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: E
authors.initials: E
authors.lastname: Gonzalez
authors.forename: S A
authors.initials: SA
authors.lastname: Anderson
authors.forename: E N
authors.initials: EN
authors.lastname: Santiago
authors.forename: K T
authors.initials: KT
authors.lastname: Stephan
authors.forename: F E
authors.initials: FE
authors.lastname: Craig
authors.forename: P
authors.initials: P
authors.lastname: O'Connell
authors.forename: V
authors.initials: V
authors.lastname: Tryon
authors.forename: R A
authors.initials: RA
authors.lastname: Clark
authors.forename: M J
authors.initials: MJ
authors.lastname: Dolan
authors.forename: S K
authors.initials: SK
authors.lastname: Ahuja
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics; D054377:Chemokine CXCL12; D018925:Chemokines / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics; D002874:Chromosome Mapping; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000503:physiopathology*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics; D001741:Black or African American
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D019713:Receptors, CCR5