Genetic acceleration of AIDS progression by a promoter variant of CCR5.
The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.
Martin
M P
MP
Science Applications International Corporation (SAIC), National Cancer Institute, Frederick MD 21702, USA.
Dean
M
M
Smith
M W
MW
Winkler
C
C
Gerrard
B
B
Michael
N L
NL
Lee
B
B
Doms
R W
RW
Margolick
J
J
Buchbinder
S
S
Goedert
J J
JJ
O'Brien
T R
TR
Hilgartner
M W
MW
Vlahov
D
D
O'Brien
S J
SJ
Carrington
M
M
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D000483:Alleles; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics; D015331:Cohort Studies; D018450:Disease Progression; D005799:Genes, Dominant; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000503:physiopathology; D015497:HIV-1; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate
C515334:CCR2 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine