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.

FIG. 1

Schematic representation of the genomic organization of the CCR2 and CCR5 genes on chromosome 3 and locations of polymorphic sites in the regulatory region of CCR5 (59029-G/A, 59353-T/C, 59356-C/T, and 59402-A/G) and in the coding regions of CCR5 (Δ32) and CCR2 (64I) genes. Open boxes indicate noncoding exons and open reading frames (ORF); lines signify introns. Exons and mutations are numbered based on the nucleotide position of the unpublished sequence with GenBank accession no. U95626. For each CCR5 polymorphism, the first letter indicates the wild-type nucleotide and the second indicates the mutant nucleotide. Numbers in parentheses indicate positions of the polymorphic sites in an alternative numbering system (19).

FIG. 2

(A) Frequency of CCR2 and CCR5 mutations among Caucasians, Hispanics, and African-Americans from all cohorts. Categorization into racial groups was determined by self-reporting. (B) Frequencies of mutant CCR5-Δ32, CCR2-64I, CCR5-59353-C, CCR5-59356-T, and CCR5-59402-G alleles in HIV-1-infected and uninfected infants (untreated category). The frequency of the CCR5-59356-T allele is significantly higher in HIV-1-infected than in uninfected infants (P = 0.002), whereas there was a trend in the association of the CCR5-59402-G allele with a decreased rate of perinatal transmission (P = 0.064). There is no significant difference (NS) in the frequencies of the CCR5-Δ32, CCR2-64I, and CCR5-59353-C alleles between the two groups.

FIG. 3

(A) Untreated African-American CCR5-59356-T mutant homozygotes have a highly significantly (P < 0.001) increased rate of HIV-1 transmission (47.6% of 21 individuals) compared to CCR5-59356-C wild-type homozygotes (13.4% of 187) or heterozygotes (14% of 71). (B) The enhancing effect of the CCR5-59356-T mutation on HIV-1 transmission was not observed in the AZT-treated group. NS, not significant.