title: Association of chemokine receptor gene (CCR2-CCR5) haplotypes with acquisition and control of HIV-1 infection in Zambians.
abstract: BACKGROUND
  Polymorphisms in chemokine (C-C motif) receptors 2 and 5 genes (CCR2 and CCR5) have been associated with HIV-1 infection and disease progression. We investigated the impact of CCR2-CCR5 haplotypes on HIV-1 viral load (VL) and heterosexual transmission in an African cohort. Between 1995 and 2006, cohabiting Zambian couples discordant for HIV-1 (index seropositive and HIV-1 exposed seronegative {HESN}) were monitored prospectively to determine the role of host genetic factors in HIV-1 control and heterosexual transmission. Genotyping for eight CCR2 and CCR5 variants resolved nine previously recognized haplotypes. By regression and survival analytic techniques, controlling for non-genetic factors, we estimated the effects of these haplotypic variants on a) index partner VL, b) seroconverter VL, c) HIV-1 transmission by index partners, d) HIV-1 acquisition by HESN partners.
  
  
  RESULTS
  Among 567 couples, 240 virologically linked transmission events had occurred through 2006. HHF*2 homozygosity was associated with significantly lower VL in seroconverters (mean beta = -0.58, log10 P = 0.027) and the HHD/HHE diplotype was associated with significantly higher VL in the seroconverters (mean beta = 0.54, log10 P = 0.014) adjusted for age and gender in multivariable model. HHD/HHE was associated with more rapid acquisition of infection by the HESNs (HR = 2.0, 95% CI = 1.20-3.43, P = 0.008), after adjustments for index partner VL and the presence of genital ulcer or inflammation in either partner in Cox multivariable models. The HHD/HHE effect was stronger in exposed females (HR = 2.1, 95% CI = 1.14-3.95, P = 0.018).
  
  
  CONCLUSIONS
  Among Zambian discordant couples, HIV-1 coreceptor gene haplotypes and diplotypes appear to modulate HIV-1 VL in seroconverters and alter the rate of HIV-1 acquisition by HESNs. These associations replicate or resemble findings reported in other African and European populations.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA. rakhi_shai@uab.edu
authors.forename: Rakhi
authors.initials: R
authors.lastname: Malhotra
authors.forename: Liangyuan
authors.initials: L
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Ilene
authors.initials: I
authors.lastname: Brill
authors.forename: Joseph
authors.initials: J
authors.lastname: Mulenga
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.forename: Sadeep
authors.initials: S
authors.lastname: Shrestha
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics*; D018450:Disease Progression; D005191:Family Characteristics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006239:Haplotypes; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D054390:Receptors, CCR2 / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics*; D019562:Viral Load; D055815:Young Adult; D015024:Zambia
chemical_list: C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5