Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 6 January 2005
Science 4 March 2005:
Vol. 307. no. 5714, pp. 1434 - 1440
DOI: 10.1126/science.1101160
Prev | Table of Contents | Next

Research Articles

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§

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.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE {varepsilon}4/{varepsilon}4 genotype accelerates HIV disease progression.
T. D. Burt, B. K. Agan, V. C. Marconi, W. He, H. Kulkarni, J. E. Mold, M. Cavrois, Y. Huang, R. W. Mahley, M. J. Dolan, et al. (2008)
PNAS 105, 8718-8723
   Abstract »    Full Text »    PDF »
Copy Number Variant Analysis of Human Embryonic Stem Cells.
H. Wu, K. J. Kim, K. Mehta, S. Paxia, A. Sundstrom, T. Anantharaman, A. I. Kuraishy, T. Doan, J. Ghosh, A. D. Pyle, et al. (2008)
Stem Cells 26, 1484-1489
   Abstract »    Full Text »    PDF »
Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion.
I. Cusco, R. Corominas, M. Bayes, R. Flores, N. Rivera-Brugues, V. Campuzano, and L. A. Perez-Jurado (2008)
Genome Res. 18, 683-694
   Abstract »    Full Text »    PDF »
Analysis of copy number variation in the rhesus macaque genome identifies candidate loci for evolutionary and human disease studies.
A. S. Lee, M. Gutierrez-Arcelus, G. H. Perry, E. J. Vallender, W. E. Johnson, G. M. Miller, J. O. Korbel, and C. Lee (2008)
Hum. Mol. Genet. 17, 1127-1136
   Abstract »    Full Text »    PDF »
The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway.
E. Frittoli, A. Palamidessi, A. Pizzigoni, L. Lanzetti, M. Garre, F. Troglio, A. Troilo, M. Fukuda, P. P. Di Fiore, G. Scita, et al. (2008)
Mol. Biol. Cell 19, 1304-1316
   Abstract »    Full Text »    PDF »
Lgals6, a 2-Million-Year-Old Gene in Mice: A Case of Positive Darwinian Selection and Presence/Absence Polymorphism.
D. Houzelstein, I. R. Goncalves, A. Orth, F. Bonhomme, and P. Netter (2008)
Genetics 178, 1533-1545
   Abstract »    Full Text »    PDF »
Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.
C McKinney, M E Merriman, P T Chapman, P J Gow, A A Harrison, J Highton, P B B Jones, L McLean, J L O'Donnell, V Pokorny, et al. (2008)
Ann Rheum Dis 67, 409-413
   Abstract »    Full Text »    PDF »
Engineering Escherichia coli heat-resistance by synthetic gene amplification.
D. Christ and J. W. Chin (2008)
Protein Eng. Des. Sel. 21, 121-125
   Abstract »    Full Text »    PDF »
Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura.
W. B. Breunis, E. van Mirre, M. Bruin, J. Geissler, M. de Boer, M. Peters, D. Roos, M. de Haas, H. R. Koene, and T. W. Kuijpers (2008)
Blood 111, 1029-1038
   Abstract »    Full Text »    PDF »
Ultrafast DNA sequencing on a microchip by a hybrid separation mechanism that gives 600 bases in 6.5 minutes.
C. P. Fredlake, D. G. Hert, C.-W. Kan, T. N. Chiesl, B. E. Root, R. E. Forster, and A. E. Barron (2008)
PNAS 105, 476-481
   Abstract »    Full Text »    PDF »
Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction.
B. Blasko, R. Kolka, P. Thorbjornsdottir, S. T. Sigurtharson, G. Sigurthsson, Z. Ronai, M. Sasvari-Szekely, S. Bothvarsson, G. Thorgeirsson, Z. Prohaszka, et al. (2008)
Int. Immunol. 20, 31-37
   Abstract »    Full Text »    PDF »
Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases.
A. J. de Smith, A. Tsalenko, N. Sampas, A. Scheffer, N. A. Yamada, P. Tsang, A. Ben-Dor, Z. Yakhini, R. J. Ellis, L. Bruhn, et al. (2007)
Hum. Mol. Genet. 16, 2783-2794
   Abstract »    Full Text »    PDF »
Optimal design of oligonucleotide microarrays for measurement of DNA copy-number.
A. J. Sharp, A. Itsara, Z. Cheng, C. Alkan, S. Schwartz, and E. E. Eichler (2007)
Hum. Mol. Genet. 16, 2770-2779
   Abstract »    Full Text »    PDF »
Ohno's dilemma: Evolution of new genes under continuous selection.
U. Bergthorsson, D. I. Andersson, and J. R. Roth (2007)
PNAS 104, 17004-17009
   Abstract »    Full Text »    PDF »
Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome.
J. O. Korbel, A. E. Urban, J. P. Affourtit, B. Godwin, F. Grubert, J. F. Simons, P. M. Kim, D. Palejev, N. J. Carriero, L. Du, et al. (2007)
Science 318, 420-426
   Abstract »    Full Text »    PDF »
Evolutionary novelties: the making and breaking of pleiotropic constraints.
F. Galis and J. A. J. Metz (2007)
Integr. Comp. Biol. 47, 409-419
   Abstract »    Full Text »    PDF »
Conserved Changes in Envelope Function during Human Immunodeficiency Virus Type 1 Coreceptor Switching.
C. Pastore, R. Nedellec, A. Ramos, O. Hartley, J. L. Miamidian, J. D. Reeves, and D. E. Mosier (2007)
J. Virol. 81, 8165-8179
   Abstract »    Full Text »    PDF »
CCR5{Delta}32 Protein Expression and Stability Are Critical for Resistance to Human Immunodeficiency Virus Type 1 In Vivo.
L. Agrawal, Q. Jin, J. Altenburg, L. Meyer, R. Tubiana, I. Theodorou, and G. Alkhatib (2007)
J. Virol. 81, 8041-8049
   Abstract »    Full Text »    PDF »
Genetic Susceptibility, HIV Infection, and the Kidney.
K. Kiryluk, J. Martino, and A. G. Gharavi (2007)
Clin. J. Am. Soc. Nephrol. 2, S25-S35
   Abstract »    Full Text »    PDF »
Systematic prediction and validation of breakpoints associated with copy-number variants in the human genome.
J. O. Korbel, A. E. Urban, F. Grubert, J. Du, T. E. Royce, P. Starr, G. Zhong, B. S. Emanuel, S. M. Weissman, M. Snyder, et al. (2007)
PNAS 104, 10110-10115
   Abstract »    Full Text »    PDF »
Evolutionary and Biomedical Insights from the Rhesus Macaque Genome.
Rhesus Macaque Genome Sequencing and Analysis Cons, R. A. Gibbs, J. Rogers, M. G. Katze, R. Bumgarner, G. M. Weinstock, E. R. Mardis, K. A. Remington, R. L. Strausberg, J. C. Venter, et al. (2007)
Science 316, 222-234
   Abstract »    Full Text »    PDF »
Postgenomic up-regulation of CCL3L1 expression in HTLV-2-infected persons curtails HIV-1 replication.
E. Pilotti, L. Elviri, E. Vicenzi, U. Bertazzoni, M. C. Re, S. Allibardi, G. Poli, and C. Casoli (2007)
Blood 109, 1850-1856
   Abstract »    Full Text »    PDF »
Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats.
J. A. L. Armour, R. Palla, P. L. J. M. Zeeuwen, M. d. Heijer, J. Schalkwijk, and E. J. Hollox (2007)
Nucleic Acids Res. 35, e19
   Abstract »    Full Text »    PDF »
Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation.
A. Mullally and J. Ritz (2007)
Blood 109, 1355-1362
   Abstract »    Full Text »    PDF »
Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees.
A. R. Rodriguez, B. P. Arulanandam, V. L. Hodara, H. M. McClure, E. K. Cobb, M. T. Salas, R. White, and K. K. Murthy (2007)
J. Gen. Virol. 88, 641-651
   Abstract »    Full Text »    PDF »
Recurrent Gene Amplification and Soft Selective Sweeps during Evolution of Multidrug Resistance in Malaria Parasites.
S. Nair, D. Nash, D. Sudimack, A. Jaidee, M. Barends, A.-C. Uhlemann, S. Krishna, F. Nosten, and T. J. C. Anderson (2007)
Mol. Biol. Evol. 24, 562-573
   Abstract »    Full Text »    PDF »
Gene Copy Number Polymorphisms in an Arbuscular Mycorrhizal Fungal Population.
N. Corradi, D. Croll, A. Colard, G. Kuhn, M. Ehinger, and I. R. Sanders (2007)
Appl. Envir. Microbiol. 73, 366-369
   Abstract »    Full Text »    PDF »
Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays.
D. Komura, F. Shen, S. Ishikawa, K. R. Fitch, W. Chen, J. Zhang, G. Liu, S. Ihara, H. Nakamura, M. E. Hurles, et al. (2006)
Genome Res. 16, 1575-1584
   Abstract »    Full Text »    PDF »
Explaining, predicting, and treating HIV-associated CD4 cell loss: after 25 years still a puzzle..
W. K. Henry, P. Tebas, and H. C. Lane (2006)
JAMA 296, 1523-1525
   Full Text »    PDF »
Genetic predisposition--is lupus nephritis a question of copy numbers?.
A. Schwarting (2006)
Nephrol. Dial. Transplant. 21, 2378-2379
   Full Text »    PDF »
Biology of CCR5 and its role in HIV infection and treatment..
M. M. Lederman, A. Penn-Nicholson, M. Cho, and D. Mosier (2006)
JAMA 296, 815-826
   Abstract »    Full Text »    PDF »
Copy number variation: New insights in genome diversity.
J. L. Freeman, G. H. Perry, L. Feuk, R. Redon, S. A. McCarroll, D. M. Altshuler, H. Aburatani, K. W. Jones, C. Tyler-Smith, M. E. Hurles, et al. (2006)
Genome Res. 16, 949-961
   Abstract »    Full Text »    PDF »
Origins of HIV and the evolution of resistance to AIDS..
J. L. Heeney, A. G. Dalgleish, and R. A. Weiss (2006)
Science 313, 462-466
   Abstract »    Full Text »    PDF »
Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission.
S. Meddows-Taylor, S. L. Donninger, M. Paximadis, D. B. Schramm, F. S. Anthony, G. E. Gray, L. Kuhn, and C. T. Tiemessen (2006)
J. Gen. Virol. 87, 2055-2065
   Abstract »    Full Text »    PDF »
Hotspots for copy number variation in chimpanzees and humans.
G. H. Perry, J. Tchinda, S. D. McGrath, J. Zhang, S. R. Picker, A. M. Caceres, A. J. Iafrate, C. Tyler-Smith, S. W. Scherer, E. E. Eichler, et al. (2006)
PNAS 103, 8006-8011
   Abstract »    Full Text »    PDF »
From the Cover: Microfabricated bioprocessor for integrated nanoliter-scale Sanger DNA sequencing.
R. G. Blazej, P. Kumaresan, and R. A. Mathies (2006)
PNAS 103, 7240-7245
   Abstract »    Full Text »    PDF »
T-bet Binding to Newly Identified Target Gene Promoters Is Cell Type-independent but Results in Variable Context-dependent Functional Effects.
K. M. Beima, M. M. Miazgowicz, M. D. Lewis, P. S. Yan, T. H-M. Huang, and A. S. Weinmann (2006)
J. Biol. Chem. 281, 11992-12000
   Abstract »    Full Text »    PDF »
Structural variants: changing the landscape of chromosomes and design of disease studies..
L. Feuk, C. R. Marshall, R. F. Wintle, and S. W. Scherer (2006)
Hum. Mol. Genet. 15, R57-R66
   Abstract »    Full Text »    PDF »
Lessons from studying monogenic disease for common disease..
L. Peltonen, M. Perola, J. Naukkarinen, and A. Palotie (2006)
Hum. Mol. Genet. 15, R67-R74
   Full Text »    PDF »
CD8+ and CD20+ Lymphocytes Cooperate To Control Acute Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimeric Virus Infections in Rhesus Monkeys: Modulation by Major Histocompatibility Complex Genotype.
H. Mao, B. A. P. Lafont, T. Igarashi, Y. Nishimura, C. Brown, V. Hirsch, A. Buckler-White, R. Sadjadpour, and M. A. Martin (2005)
J. Virol. 79, 14887-14898
   Abstract »    Full Text »    PDF »
A Novel Gene Family NBPF: Intricate Structure Generated by Gene Duplications During Primate Evolution.
K. Vandepoele, N. Van Roy, K. Staes, F. Speleman, and F. van Roy (2005)
Mol. Biol. Evol. 22, 2265-2274
   Abstract »    Full Text »    PDF »
Use of a Combined Ex Vivo/In Vivo Population Approach for Screening of Human Genes Involved in the Human Immunodeficiency Virus Type 1 Life Cycle for Variants Influencing Disease Progression.
G. Bleiber, M. May, R. Martinez, P. Meylan, J. Ott, J. S. Beckmann, A. Telenti, and the Swiss HIV Cohort Study (2005)
J. Virol. 79, 12674-12680
   Abstract »    Full Text »    PDF »
Combined Effect of CCR5-{Delta}32 Heterozygosity and the CCR5 Promoter Polymorphism -2459 A/G on CCR5 Expression and Resistance to Human Immunodeficiency Virus Type 1 Transmission.
F. Hladik, H. Liu, E. Speelmon, D. Livingston-Rosanoff, S. Wilson, P. Sakchalathorn, Y. Hwangbo, B. Greene, T. Zhu, and M. J. McElrath (2005)
J. Virol. 79, 11677-11684
   Abstract »    Full Text »    PDF »
Genetic Influences on Health: Does Race Matter?.
M. Bamshad (2005)
JAMA 294, 937-946
   Abstract »    Full Text »    PDF »
Multiple Products Derived from Two CCL4 Loci: High Incidence of a New Polymorphism in HIV+ Patients.
R. Colobran, P. Adreani, Y. Ashhab, A. Llano, J. A. Este, O. Dominguez, R. Pujol-Borrell, and M. Juan (2005)
J. Immunol. 174, 5655-5664
   Abstract »    Full Text »    PDF »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)