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Submitted on June 7, 2004
Accepted on December 22, 2004
The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility
Enrique Gonzalez 1, Hemant Kulkarni 1, Hector Bolivar 1, Andrea Mangano 2, Racquel Sanchez 1, Gabriel Catano 1, Robert J. Nibbs 3, Barry I. Freedman 4, Marlon P. Quinones 1, Michael J. Bamshad 5, Krishna K. Murthy 6, Brad H. Rovin 7, William Bradley 8, Robert A. Clark 1, Stephanie A. Anderson 8, Robert J. O'Connell 9, Brian K. Agan 9, Seema S. Ahuja 1, Rosa Bologna 10, Luisa Sen 2, Matthew J. Dolan 11*, Sunil K. Ahuja 1*
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, Hospital de Pediatría "J.P. Garrahan," Buenos Aires, Argentina. 3 Cancer Research UK Beatson Laboratories, Glasgow, Scotland, G61 1BD. 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; Tri-Service AIDS Clinical Consortium, Wilford Hall Medical Center, Lackland AFB, TX 78236, USA. 9 Tri-Service AIDS Clinical Consortium; Infectious Diseases Service, Wilford Hall Medical Center, Lackland AFB, TX 78236, USA. 10 Servicio de Infectología, Hospital de Pediatría "J.P. Garrahan," Buenos Aires, Argentina. 11 Tri-Service AIDS Clinical Consortium; Infectious Diseases Service, Wilford Hall Medical Center, Lackland AFB, TX 78236, USA; Defense Institute for Medical Operations, Brooks City-Base, TX 78235, USA.
* To whom correspondence should be addressed.
Matthew J. Dolan , E-mail: matthew.dolan{at}lackland.af.mil Sunil K. Ahuja , E-mail: ahujas{at}uthscsa.edu
Segmental duplications in the human genome are selectively enrichedfor genes involved in immunity, although the phenotypic consequencesfor host defense are unknown. We show that there are significantinterindividual and interpopulation differences in the copynumber of a segmental duplication encompassing the gene encodingCCL3L1 (MIP-1 P), a potent HIV-1-suppressive chemokine and ligandfor the HIV coreceptor CCR5. Possession of a CCL3L1 copy numberlower than the population average is associated with markedlyenhanced HIV/AIDS susceptibility. This susceptibility is evengreater in individuals who also possess disease-acceleratingCCR5 genotypes. This relationship between CCL3L1 dose and alteredHIV/AIDS susceptibility points to a central role for CCL3L1in HIV/AIDS pathogenesis, and indicates that differences inthe dose of immune response genes may constitute a genetic basisfor variable responses to infectious diseases.
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P), a potent 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/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.
