title: African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine.
abstract: 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.
authors: Gertrude H. Sergievsky Centre, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. ik24@columbia.edu
authors: Louise
authors: L
authors: Kuhn
authors: Diana B
authors: DB
authors: Schramm
authors: Samantha
authors: S
authors: Donninger
authors: Stephen
authors: S
authors: Meddows-Taylor
authors: Ashraf H
authors: AH
authors: Coovadia
authors: Gayle G
authors: GG
authors: Sherman
authors: Glenda E
authors: GE
authors: Gray
authors: Caroline T
authors: CT
authors: Tiemessen
mesh_terms: 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
chemical_list: 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
references: Blood. 2000 Jan 15;95(2):715-8
references: 10627485
references: Nat Immunol. 2007 Mar;8(3):219-22
references: 17304227
references: Clin Exp Immunol. 2001 Mar;123(3):443-50
references: 11298132
references: AIDS Res Hum Retroviruses. 2001 Jul 1;17(10):925-35
references: 11461678
references: Lancet. 2002 Apr 6;359(9313):1178-86
references: 11955535
references: Science. 2002 Aug 9;297(5583):1003-7
references: 12169732
references: Eur J Immunol. 2002 Oct;32(10):3016-26
references: 12355456
references: Lancet. 2003 Sep 13;362(9387):859-68
references: 13678973
references: AIDS. 2003 Sep 26;17(14):2053-61
references: 14502008
references: J Clin Invest. 1991 Jun;87(6):1916-24
references: 1904068
references: AIDS. 1997 Mar 15;11(4):437-44
references: 9084790
references: J Immunol. 1999 Apr 1;162(7):4355-64
references: 10201969
references: AIDS. 2004 Oct 21;18(15):2009-17
references: 15577622
references: Science. 2005 Mar 4;307(5714):1434-40
references: 15637236
references: AIDS. 2005 Aug 12;19(12):1289-97
references: 16052084
references: AIDS. 2005 Sep 2;19(13):1415-22
references: 16103773
references: Curr HIV/AIDS Rep. 2006 Feb;3(1):13-9
references: 16522254
references: J Gen Virol. 2006 Jul;87(Pt 7):2055-65
references: 16760409
references: J Acquir Immune Defic Syndr. 2006 Aug 15;42(5):545-53
references: 16837862
references: J Infect Dis. 2006 Oct 15;194(8):1089-97
references: 16991083
references: Semin Immunol. 2006 Dec;18(6):387-403
references: 16978874
references: Lancet Infect Dis. 2006 Nov;6(11):726-32
references: 17067921
references: AIDS. 2000 Aug 18;14(12):1721-9
references: 10985308