Combinatorial content of CCL3L and CCL4L gene copy numbers influence HIV-AIDS susceptibility in Ukrainian children.
OBJECTIVE
CCL3L and CCL4L genes encode HIV-suppressive chemokines, colocalize on chromosome 17q12 and have copy number variation. Copy number variation of CCL3L associates with HIV-AIDS susceptibility. Here, we determined the influence of the combinatorial content of distinct CCL3L and CCL4L genes on HIV-AIDS susceptibility.


METHODS
By designing gene-specific assays, the association between doses of all CCL3L or CCL4L genes or their individual duplicated components (CCL3La/b and CCL4La/b) with HIV-AIDS susceptibility was determined in 298 perinatally exposed Ukrainian children.


RESULTS
The odds of transmission was increased in children with less than two copies of CCL3L or CCL4L, compared with those with at least two copies, and 10-fold higher when both mother and offspring had less than two CCL3L or CCL4L copies, compared with mother-child pairs with at least two copies. The extent of the pair-wise correlations between CCL3La, CCL3Lb, CCL4La and CCL4Lb copy number varied extensively, with an inverse correlation between CCL4L genes that transcribe a classical chemokine (CCL4La) versus aberrantly-spliced transcripts (CCL4Lb). Children possessing only CCL4Lb progressed four times faster to AIDS than those with only CCL4La. A lower content of CCL3L and CCL4L genes that transcribe classical chemokines was associated with enhanced HIV-AIDS susceptibility.


CONCLUSIONS
Transmission risk is greatest when mother and offspring both have low CCL3L or CCL4L gene doses. The impact on HIV-AIDS susceptibility of the chemokine gene-rich locus on 17q12 is dependent on the balance between the doses of genes conferring protective (CCL3La and CCL4La) versus detrimental (CCL4Lb) effects. Hence, the combinatorial genomic content of distinct genes within a copy number variable region may determine disease susceptibility.
Shostakovich-Koretskaya
Ludmila
L
Department of General Pediatrics and Pediatric Infectious Diseases, Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.
Catano
Gabriel
G
Chykarenko
Zoya A
ZA
He
Weijing
W
Gornalusse
German
G
Mummidi
Srinivas
S
Sanchez
Racquel
R
Dolan
Matthew J
MJ
Ahuja
Seema S
SS
Clark
Robert A
RA
Kulkarni
Hemant
H
Ahuja
Sunil K
SK
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics; D054405:Chemokine CCL3 / Q000235:genetics*; D054407:Chemokine CCL4 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics* / Q000635:transmission; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D016133:Polymerase Chain Reaction / Q000379:methods; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics; D009626:Terminology as Topic
D054405:Chemokine CCL3; D054407:Chemokine CCL4