Michael W. Smith,
*
Michael Dean,
*
Mary Carrington,
*
Cheryl Winkler,
Gavin A. Huttley,
Deborah A. Lomb,
James J. Goedert,
Thomas R. O'Brien,
Lisa P. Jacobson,
Richard Kaslow,
Susan Buchbinder,
Eric Vittinghoff,
David Vlahov,
Keith Hoots,
Margaret W. Hilgartner,
Hemophilia Growth and Development
Study (HGDS),
Multicenter AIDS Cohort Study (MACS), Multicenter
Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study,
Stephen J. O'Brien
The critical role of chemokine receptors (CCR5 and CXCR4) in human
immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes
that mediate HIV-1 disease progression. A mutation
(CCR2-64I) within the first transmembrane region of the
CCR2 chemokine and HIV-1 receptor gene is described that
occurred at an allele frequency of 10 to 15 percent among Caucasians
and African Americans. Genetic association analysis of five acquired
immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that
although CCR2-64I exerts no influence on the incidence of
HIV-1 infection, HIV-1-infected individuals carrying the
CCR2-64I allele progressed to AIDS 2 to 4 years
later than individuals homozygous for the common allele. Because
CCR2-64I occurs invariably on a CCR5-+-bearing
chromosomal haplotype, the independent effects of
CCR5-
32 (which also delays AIDS onset) and
CCR2-64I were determined. An estimated 38 to 45 percent of
AIDS patients whose disease progresses rapidly (less than 3 years until
onset of AIDS symptoms after HIV-1 exposure) can be attributed to their
CCR2-+/+ or CCR5-+/+ genotype, whereas the
survival of 28 to 29 percent of long-term survivors, who avoid AIDS for
16 years or more, can be explained by a mutant genotype for
CCR2 or CCR5.
M. W. Smith, M. Carrington, C. Winkler, D. A. Lomb,
Science Applications International Corp. Frederick, National Cancer
Institute, Frederick, MD 21702-1201, USA.
M. Dean, G. A. Huttley, S. J. O'Brien, Laboratory of Genomic
Diversity, National Cancer Institute, Frederick, MD 21702-1201, USA.
J. J. Goedert and T. R. O'Brien, Viral Epidemiology Branch,
National Cancer Institute-Executive Plaza North, 6130 Executive Boulevard, Bethesda, MD 20892, USA.
L. P. Jacobson, Department of Epidemiology, The Johns Hopkins
University School of Hygiene and Public Health, Room E-7008, 615 North
Wolfe Street, Baltimore, MD 21205-1999, USA.
R. Kaslow, Department of Epidemiology, University of Alabama at
Birmingham, 720 South 20th Street, Tidwell Hall 212C, Birmingham, AL
35294, USA.
S. Buchbinder and E. Vittinghoff, AIDS Office, Department of Public
Health, 25 Van Ness Avenue, Suite 500, San Francisco, CA 94102-6033,
USA.
D. Vlahov, Department of Epidemiology, The Johns Hopkins School of
Hygiene and Public Health, Room E-6008, 615 North Wolfe Street,
Baltimore, MD 21205, USA.
K. Hoots, Departments of Pediatrics and Internal Medicine, University
of Texas Medical School at Houston, Houston, TX 77030, USA.
M. W. Hilgartner, Division of Pediatric Hematology and Oncology,
New York Hospital-Cornell Medical Center, 525 East 68th Street, Payson
695, New York, NY 10021, USA.
*
These authors contributed equally to this study.
To whom correspondence should be addressed. E-mail:
obrien{at}ncifcrf.gov
