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African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine

Kuhn, Louisea; Schramm, Diana Bb; Donninger, Samanthab; Meddows-Taylor, Stephenb; Coovadia, Ashraf Hc; Sherman, Gayle Gd; Gray, Glenda Ee; Tiemessen, Caroline Tb

doi: 10.1097/QAD.0b013e3282ba553a
Clinical Science

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.

Method: 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 (∼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.

Conclusion: 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.

From the aGertrude H. Sergievsky Centre, College of Physicians and Surgeons and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA

bAIDS Virus Research Unit, National Institute for Communicable Diseases, and University of the Witwatersrand, Johannesburg, South Africa

cCoronation Hospital, Wits Paediatric HIV Clinics, Johannesburg, South Africa

dNational Health Laboratory Services and University of the Witwatersrand, Department of Molecular Medicine and Haematology, Johannesburg, South Africa

ePerinatal HIV Research Unit, Chris Hani Baragwanath Hospital, Soweto, South Africa.

Received 12 February, 2007

Revised 19 April, 2007

Accepted 22 April, 2007

Correspondence to Louise Kuhn, Sergievsky Centre, Columbia University, 630 W 168th Street, New York, New York 10032, USA. E-mail: ik24@columbia.edu

© 2007 Lippincott Williams & Wilkins, Inc.