title: A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants.
abstract: There are natural mutations in the coding and noncoding regions of the human immunodeficiency virus type 1 (HIV-1) CC-chemokine coreceptor 5 (CCR5) and in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygous for the CCR5-Delta32 allele, which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5' regulatory region, some of which influence the rate of disease progression in adult AIDS study cohorts. We genotyped 1,442 infants (1,235 uninfected and 207 HIV-1 infected) for five CCR5 and CCR2 polymorphisms: CCR5-59353-T/C, CCR5-59356-C/T CCR5-59402-A/G, CCR5-Delta32, and CCR2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 AZT-untreated mother-infant pairs (554 uninfected and 113 HIV-1 infected). We found that the mutant CCR5-59356-T allele is relatively common in African-Americans (20.6% allele frequency among 552 infants) and rare in Caucasians and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively; P < 0.001). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were African-Americans. Among the African-American infants in the AZT-untreated group, there was a highly significant increase in HIV-1 transmission to infants with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those with no or one mutant allele (13.4 to 14.1% of 187 and 71, respectively; P < 0.001). The increased relative risk was 5.9 (95% confidence interval, 2.3 to 15.3; P < 0.001). The frequency of the CCR5-59356-T mutation varies between population groups in the United States, a low frequency occurring in Caucasians and a higher frequency occurring in African-Americans. Homozygosity for CCR5-59356-T is strongly associated with an increased rate of perinatal HIV-1 transmission.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York.
authors.forename: L G
authors.initials: LG
authors.lastname: Kostrikis
authors.forename: A U
authors.initials: AU
authors.lastname: Neumann
authors.forename: B
authors.initials: B
authors.lastname: Thomson
authors.forename: B T
authors.initials: BT
authors.lastname: Korber
authors.forename: P
authors.initials: P
authors.lastname: McHardy
authors.forename: R
authors.initials: R
authors.lastname: Karanicolas
authors.forename: L
authors.initials: L
authors.lastname: Deutsch
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: J F
authors.initials: JF
authors.lastname: Lew
authors.forename: K
authors.initials: K
authors.lastname: McIntosh
authors.forename: H
authors.initials: H
authors.lastname: Pollack
authors.forename: W
authors.initials: W
authors.lastname: Borkowsky
authors.forename: H M
authors.initials: HM
authors.lastname: Spiegel
authors.forename: P
authors.initials: P
authors.lastname: Palumbo
authors.forename: J
authors.initials: J
authors.lastname: Oleske
authors.forename: A
authors.initials: A
authors.lastname: Bardeguez
authors.forename: K
authors.initials: K
authors.lastname: Luzuriaga
authors.forename: J
authors.initials: J
authors.lastname: Sullivan
authors.forename: S M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: R A
authors.initials: RA
authors.lastname: Koup
authors.forename: D D
authors.initials: DD
authors.lastname: Ho
authors.forename: J P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D001741:Black or African American; D000483:Alleles; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000635:transmission*; D015497:HIV-1; D006630:Hispanic or Latino; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D015810:Linkage Disequilibrium; D018743:Perinatal Care; D011110:Polymorphism, Genetic; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000145:classification / Q000235:genetics*; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D044465:White People; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D020121:5' Untranslated Regions; D019380:Anti-HIV Agents; C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015215:Zidovudine