Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.
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.
Mummidi
S
S
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.
Ahuja
S S
SS
Gonzalez
E
E
Anderson
S A
SA
Santiago
E N
EN
Stephan
K T
KT
Craig
F E
FE
O'Connell
P
P
Tryon
V
V
Clark
R A
RA
Dolan
M J
MJ
Ahuja
S K
SK
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
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D019713:Receptors, CCR5