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Science 307 (5714): 1434-1440

Copyright © 2005 by the American Association for the Advancement of Science

The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility

Enrique Gonzalez,1* Hemant Kulkarni,1* Hector Bolivar,1*{dagger} Andrea Mangano,2* Racquel Sanchez,1{ddagger} Gabriel Catano,1{ddagger} Robert J. Nibbs,3{ddagger} Barry I. Freedman,4{ddagger} Marlon P. Quinones,1{ddagger} Michael J. Bamshad,5 Krishna K. Murthy,6 Brad H. Rovin,7 William Bradley,8,9 Robert A. Clark,1 Stephanie A. Anderson,8,9 Robert J. O'Connell,9,10 Brian K. Agan,9,10 Seema S. Ahuja,1 Rosa Bologna,11 Luisa Sen,2 Matthew J. Dolan,9,10,12§ Sunil K. Ahuja1§

Abstract: Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1{alpha}P), a potent human immunodeficiency virus–1 (HIV-1)–suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.

1 Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, and Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
2 Laboratorio de Biología Celular y Retrovirus–Consejo Nacional de Investigaciones Científicus y Tecnicas, Hospital de Pediatría "J. P. Garrahan," 1245 Buenos Aires, Argentina.
11 Servicio de Infectología, Hospital de Pediatría "J. P. Garrahan," 1245 Buenos Aires, Argentina.
3 Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, Scotland, UK.
4 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
5 Departments of Human Genetics and Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.
6 Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA.
7 Division of Nephrology, Ohio State University, Columbus, OH 43210, USA.
8 Henry M. Jackson Foundation, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236, USA.
9 Tri-Service AIDS Clinical Consortium, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236, USA.
10 Infectious Diseases Service, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236, USA.
12 Defense Institute for Medical Operations, Brooks City-Base, TX 78235, USA.

* These authors contributed equally to this work.

{dagger} Present address: AIDS Clinical Research Unit, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

{ddagger} These authors contributed equally to this work.

§ To whom correspondence should be addressed. E-mail: ahujas{at}uthscsa.edu (S.K.A.); matthew.dolan{at}brooks.af.mil (M.J.D.)

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