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

There are natural mutations in the coding and noncoding regions of the huma n immunodeficiency virus type I (HIV-1) CC-chemokine coreceptor 5 (CCR5) an d in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygo us for the CCR5-Delta 32 allele, a which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5' regulatory region, same 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 polymorph isms: CCR5-59353-T/C, CCR5-59356-C/T CCR5-59402-A/G, CCR5-Delta 32, and CCR 2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 A ZT-untreated mother-infant pairs (554 uninfected and 113 HIV-1 infected). W e found that the mutant CCR5-59356-T allele is relatively common in African -Americans (20.6% allele frequency among 552 infants) and rare in Caucasian s and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively; P < 0.0 01). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were Afr ican-Americans. Among the African-American infants in the AZT-untreated gro up? there was a highly significant increase in HIV-1 transmission to infant s with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those wit h 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 betwee n population groups in the United States, a low frequency occurring in Cauc asians 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.