African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine.
BACKGROUND
Individuals with more copies of CCL3L1 (CCR5 ligand) than their population median have been found to be less susceptible to HIV infection. We investigated whether maternal or infant CCL3L1 gene copy numbers are associated with perinatal HIV transmission when single-dose nevirapine is given for prevention.


METHODS
A nested case-control study was undertaken combining data from four cohorts including 849 HIV-infected mothers and their infants followed prospectively in Johannesburg, South Africa. Access to antiretroviral drugs for the prevention of perinatal transmission differed across the cohorts. Maternal and infant CCL3L1 gene copy numbers per diploid genome (pdg) were determined by real-time polymerase chain reaction for 79 out of 83 transmitting pairs ( approximately 10% transmission rate) and 235 randomly selected non-transmitting pairs.


RESULTS
Higher numbers of infant, but not maternal, CCL3L1 gene copies were associated with reduced HIV transmission (P = 0.004) overall, but the association was attenuated if mothers took single-dose nevirapine or if the maternal viral load was low. Maternal nevirapine was also associated with reduced spontaneously released CCL3 (P = 0.007) and phytohemagglutinin-stimulated CCL3 (P = 0.005) production in cord blood mononuclear cells from uninfected infants.


CONCLUSIONS
We observed a strong association between higher infant CCL3L1 gene copies and reduced susceptibility to HIV in the absence of maternal nevirapine. We also observed a reduction in newborn CCL3 production with nevirapine exposure. Taken together, we hypothesize that nevirapine may have direct or indirect effects that partly modify the role of the CCR5 ligand CCL3 in HIV transmission, obscuring the relationship between this genetic marker and perinatal HIV transmission.
Kuhn
Louise
L
Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. ik24@columbia.edu
Schramm
Diana B
DB
Donninger
Samantha
S
Meddows-Taylor
Stephen
S
Coovadia
Ashraf H
AH
Sherman
Gayle G
GG
Gray
Glenda E
GE
Tiemessen
Caroline T
CT
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000235:genetics* / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D019829:Nevirapine / Q000627:therapeutic use*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019562:Viral Load
D019380:Anti-HIV Agents; C515429:CCL3 protein, human; C066507:CCL4 protein, human; C483024:CCL5 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine
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