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Science 16 January 1998:
Vol. 279. no. 5349, pp. 389 - 393
DOI: 10.1126/science.279.5349.389
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Reports

Genetic Restriction of AIDS Pathogenesis by an SDF-1 Chemokine Gene Variant

Cheryl Winkler, William Modi, Michael W. Smith, George W. Nelson, Xueyun Wu, Mary Carrington, Michael Dean, Tasaku Honjo, Kai Tashiro, D. Yabe, Susan Buchbinder, Eric Vittinghoff, James J. Goedert, Thomas R. O'Brien, Lisa P. Jacobson, Roger Detels, Sharyne Donfield, Anne Willoughby, Edward Gomperts, David Vlahov, John Phair, ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), Stephen J. O'Brien *

Stromal-derived factor (SDF-1) is the principal ligand for CXCR4, a coreceptor with CD4 for T lymphocyte cell line-tropic human immunodeficiency virus-type 1 (HIV-1). A common polymorphism, SDF1-3'A, was identified in an evolutionarily conserved segment of the 3' untranslated region of the SDF-1 structural gene transcript. In the homozygous state, SDF1-3'A/3'A delays the onset of acquired immunodeficiency syndrome (AIDS), according to a genetic association analysis of 2857 patients enrolled in five AIDS cohort studies. The recessive protective effect of SDF1-3'A was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants in these populations, and was complementary with these mutations in delaying the onset of AIDS.

C. Winkler, W. Modi, M. W. Smith, G. W. Nelson, X. Wu, M. Carrington, Science Applications International Corporation (SAIC), National Cancer Institute, Frederick, MD 21702, USA.
M. Dean and S. J. O'Brien, Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702, USA.
T. Honjo and D. Yabe, Department of Medical Chemistry, Kyoto University, Kyoto, Japan.
K. Tashiro, Center for Molecular Biology and Genetics, Kyoto University, Kyoto, Japan.
S. Buchbinder and E. Vittinghoff, AIDS Office, Department of Public Health, 25 Van Ness Avenue, Suite 500, San Francisco, CA 94102, 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, CAMACS, Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Room E-7006, 615 North Wolfe Street, Baltimore, MD 21205, USA.
R. Detels, UCLA School of Public Health, Department of Epidemiology, Center for Health Sciences, Room 71-267, Box 951772, Los Angeles, CA 90095, USA.
S. Donfield, Rho Inc., 121 South Estes Drive, Suite 100, Chapel Hill, NC 27514, USA.
A. Willoughby, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, Building 61E, Room 4B11H, Bethesda, MD 20892, USA.
E. Gomperts, Children's Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
D. Vlahov, Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Room E-6008, 615 North Wolfe Street, Baltimore, MD 21205, USA.
J. Phair, Northwestern University Medical School, Comprehensive AIDS Center, 6980 North Lake Shore Drive, Suite 1106, Chicago, IL 60611, USA.
*   To whom correspondence should be addressed.

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J. Immunol. 162, 5986-5992
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Current Concepts in Human Immunodeficiency Virus Infection and AIDS.
S. A. Schwartz and M. P. N. Nair (1999)
Clin. Vaccine Immunol. 6, 295-305
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Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages.
B. Lee, M. Sharron, L. J. Montaner, D. Weissman, and R. W. Doms (1999)
PNAS 96, 5215-5220
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Polymorphism in chemokine promoter affects HIV-1 disease progression.
H. Liu, D. Chao, E. E. Nakayama, H. Taguchi, M. Goto, X. Xin, J.-k. Takamatsu, H. Saito, Y. Ishikawa, T. Akaza, et al. (1999)
PNAS 96, 4581-4585
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Identification of CXCR4 Domains That Support Coreceptor and Chemokine Receptor Functions.
B. J. Doranz, M. J. Orsini, J. D. Turner, T. L. Hoffman, J. F. Berson, J. A. Hoxie, S. C. Peiper, L. F. Brass, and R. W. Doms (1999)
J. Virol. 73, 2752-2761
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Chemokine and Chemokine Receptor Gene Variants and Risk of Non-Hodgkin's Lymphoma in Human Immunodeficiency Virus-1-Infected Individuals.
C. S. Rabkin, Q.-e. Yang, J. J. Goedert, G. Nguyen, H. Mitsuya, and S. Sei (1999)
Blood 93, 1838-1842
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Induction of autoantibodies to mouse CCR5 with recombinant papillomavirus particles.
B. Chackerian, D. R. Lowy, and J. T. Schiller (1999)
PNAS 96, 2373-2378
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CCR2-64I Polymorphism Is Not Associated with Altered CCR5 Expression or Coreceptor Function.
R. Mariani, S. Wong, L. C. F. Mulder, D. A. Wilkinson, A. L. Reinhart, G. LaRosa, R. Nibbs, T. R. O'Brien, N. L. Michael, R. I. Connor, et al. (1999)
J. Virol. 73, 2450-2459
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cAMP Up-Regulates Cell Surface Expression of Lymphocyte CXCR4: Implications for Chemotaxis and HIV-1 Infection.
S. W. Cole, B. D. Jamieson, and J. A. Zack (1999)
J. Immunol. 162, 1392-1400
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Combined Genotypes of CCR5, CCR2, SDF1, and HLA Genes Can Predict the Long-Term Nonprogressor Status in Human Immunodeficiency Virus-1-Infected Individuals.
M. Magierowska, I. Theodorou, P. Debre, F. Sanson, B. Autran, Y. Riviere, D. Charron, F. ALT, I. S. Groups, and D. Costagliola (1999)
Blood 93, 936-941
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Activity of Different Bicyclam Derivatives against Human Immunodeficiency Virus Depends on Their Interaction with the CXCR4 Chemokine Receptor.
J. A. Esté, C. Cabrera, E. De Clercq, S. Struyf, J. Van Damme, G. Bridger, R. T. Skerlj, M. J. Abrams, G. Henson, A. Gutierrez, et al. (1999)
Mol. Pharmacol. 55, 67-73
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