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

• Published in: AIDS (London) Vol. 21; no. 13; pp. 1753 - 1761
• Main Authors: KUHN, Louise, SCHRAMM, Diana B, DONNINGER, Samantha, MEDDOWS-TAYLOR, Stephen, COOVADIA, Ashraf H, SHERMAN, Gayle G, GRAY, Glenda E, TIEMESSEN, Caroline T
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 20-08-2007
• Subjects: Adult; AIDS/HIV; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Case-Control Studies; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC - biosynthesis; Chemokines, CC - genetics; Female; Fetal Blood - metabolism; Genetic Predisposition to Disease; HIV Infections - genetics; HIV Infections - prevention & control; HIV Infections - transmission; HIV Infections - virology; Human immunodeficiency virus; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infant, Newborn; Infectious Disease Transmission, Vertical; Infectious diseases; Male; Medical sciences; Nevirapine - therapeutic use; Pharmacology. Drug treatments; Pregnancy; Pregnancy Complications, Infectious - virology; Reverse Transcriptase Inhibitors - therapeutic use; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Load; South Africa; Africa; Antiretroviral agent; RNA-directed DNA polymerase; Nevirapine; Non nucleoside compound; Infant; Phytohemagglutinin; Maternal diseases; Microbiological investigation; Reverse transcriptase inhibitor; Antiviral; Viral load; Child; Human; Immunopathology; Enzyme; Transferases; Enzyme inhibitor; AIDS; chemokines; Immune deficiency; Infection; Chemokine; Polymerase chain reaction; Nucleotidyltransferases; Newborn; Viral disease; Vertical transmission; CCL3/MIP1alpha; mother-to-child HIV transmission; Molecular biology
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/qad.0b013e3282ba553a

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.
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.
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.
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.