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Journal of Virology, December 1999, p. 10264-10271, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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

Leondios G. Kostrikis,1,* Avidan U. Neumann,2 Bruce Thomson,3 Bette T. Korber,4 Paul McHardy,1 Rose Karanicolas,1 Lisa Deutsch,2 Yaoxing Huang,1 Judy F. Lew,5 Kenneth McIntosh,6 Henry Pollack,7 William Borkowsky,7 Hans M. L. Spiegel,1 Paul Palumbo,8 James Oleske,8 Arlene Bardeguez,8 Katherine Luzuriaga,9 John Sullivan,9 Steven M. Wolinsky,10 Richard A. Koup,11 David D. Ho,1 and John P. Moore1

Aaron Diamond AIDS Research Center, The Rockefeller University,1 and New York University Medical Center,7 New York, New York; Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel2; Clinical Trials and Surveys Corporation, Baltimore, Maryland3; Los Alamos National Laboratory, Los Alamos, New Mexico4; Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland5; Department of Pediatrics, Harvard Medical School, Boston,6 and University of Massachusetts Medical School, Worcester,9 Massachusetts; Department of Pediatrics, UMDNJ Medical School, Newark, New Jersey8; Department of Medicine, Northwestern University Medical School, Chicago, Illinois10; and Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas11

Received 19 July 1999/Accepted 7 September 1999

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-Delta 32 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-Delta 32, 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.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, 455 First Ave., New York, NY 10016. Phone: (212) 448-5021. Fax: (212) 725-1126. E-mail: lkostrik{at}adarc.org.

Journal of Virology, December 1999, p. 10264-10271, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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