title: Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy.
abstract: BACKGROUND
  Both the natural history of HIV infection and the response to antiretroviral therapy are heterogeneous. Polymorphisms in chemokine receptor genes modulate the natural history of HIV-1 infection. In comparison with subjects with other genotypes, the prognosis for HIV-1-infected CCR5-delta32 heterozygotes is more favorable and that for CCR5 promoter allele 59029A homozygotes is less favorable.
  
  
  METHODS
  HIV-1-infected adults with a CD4+ lymphocyte count > or = 200 cells x 10(6)/l and a plasma HIV RNA level > or = 1000 copies/ml were treated with indinavir, zidovudine and lamivudine for 6 months. HIV RNA levels were measured at 4-week intervals. Genotyping for chemokine receptor gene polymorphisms (CCR5-delta32, CCR5 59029A/G, CCR2-641) was performed. We examined whether the time to first HIV RNA < 200 copies/ml, frequency of viral suppression failure (HIV RNA > or = 200 copies/ml between weeks 16 and 28 of therapy), or reduction from the pre-treatment HIV RNA level differed by genotype.
  
  
  RESULTS
  Time to first HIV RNA < 200 copies/ml was not predicted by genotype. Among 272 Caucasian patients, viral suppression failure was more common among patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype (28%) than among all other subjects combined (relative risk, 2.0; P = 0.06). After 24 weeks of therapy, genotype groups differed in the reduction of the HIV RNA level from baseline (P = 0.02); patients with the CCR5 +/+ ¿ CCR2+/+ ¿ CCR5-59029 A/A genotype had a mean reduction of 2.12 log10 copies/ml compared to 2.64 log10 copies/ml among all other groups combined.
  
  
  CONCLUSIONS
  Polymorphisms in chemokine receptor genes may explain some of the heterogeneity in sustaining viral suppression observed among patients receiving potent antiretroviral therapy.
authors.affiliation: Viral Epidemiology Branch, National Cancer Institute, Bethesda, Maryland, USA. obrient@exchange.nih.gov
authors.forename: T R
authors.initials: TR
authors.lastname: O'Brien
authors.forename: D H
authors.initials: DH
authors.lastname: McDermott
authors.forename: J P
authors.initials: JP
authors.lastname: Ioannidis
authors.forename: M
authors.initials: M
authors.lastname: Carrington
authors.forename: P M
authors.initials: PM
authors.lastname: Murphy
authors.forename: D V
authors.initials: DV
authors.lastname: Havlir
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
mesh_terms: D000328:Adult; D000483:Alleles; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D019259:Lamivudine / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012367:RNA, Viral / Q000097:blood; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; C515334:CCR2 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012367:RNA, Viral; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir