The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.
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-1alphaP), 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.
Gonzalez
Enrique
E
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.
Kulkarni
Hemant
H
Bolivar
Hector
H
Mangano
Andrea
A
Sanchez
Racquel
R
Catano
Gabriel
G
Nibbs
Robert J
RJ
Freedman
Barry I
BI
Quinones
Marlon P
MP
Bamshad
Michael J
MJ
Murthy
Krishna K
KK
Rovin
Brad H
BH
Bradley
William
W
Clark
Robert A
RA
Anderson
Stephanie A
SA
O'connell
Robert J
RJ
Agan
Brian K
BK
Ahuja
Seema S
SS
Bologna
Rosa
R
Sen
Luisa
L
Dolan
Matthew J
MJ
Ahuja
Sunil K
SK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D018450:Disease Progression; D005006:Ethnicity / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D002679:Pan troglodytes / Q000235:genetics; D010641:Phenotype; D011634:Public Health; D044469:Racial Groups / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D019713:Receptors, CCR5