title: Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.
abstract: BACKGROUND
  CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk.
  
  
  METHODS
  Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk.
  
  
  RESULTS
  CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors.
  
  
  CONCLUSIONS
  The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Zimmerman
authors.forename: A
authors.initials: A
authors.lastname: Buckler-White
authors.forename: G
authors.initials: G
authors.lastname: Alkhatib
authors.forename: T
authors.initials: T
authors.lastname: Spalding
authors.forename: J
authors.initials: J
authors.lastname: Kubofcik
authors.forename: C
authors.initials: C
authors.lastname: Combadiere
authors.forename: D
authors.initials: D
authors.lastname: Weissman
authors.forename: O
authors.initials: O
authors.lastname: Cohen
authors.forename: A
authors.initials: A
authors.lastname: Rubbert
authors.forename: G
authors.initials: G
authors.lastname: Lam
authors.forename: M
authors.initials: M
authors.lastname: Vaccarezza
authors.forename: P E
authors.initials: PE
authors.lastname: Kennedy
authors.forename: V
authors.initials: V
authors.lastname: Kumaraswami
authors.forename: J V
authors.initials: JV
authors.lastname: Giorgi
authors.forename: R
authors.initials: R
authors.lastname: Detels
authors.forename: J
authors.initials: J
authors.lastname: Hunter
authors.forename: M
authors.initials: M
authors.lastname: Chopek
authors.forename: E A
authors.initials: EA
authors.lastname: Berger
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
authors.forename: T B
authors.initials: TB
authors.lastname: Nutman
authors.forename: P M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics; D003001:Cloning, Molecular; D018450:Disease Progression; D004198:Disease Susceptibility; D016368:Frameshift Mutation / Q000235:genetics; D005787:Gene Frequency; D015658:HIV Infections; D018023:HIV Seronegativity / Q000235:genetics*; D015497:HIV-1; D006367:HeLa Cells; D006579:Heterozygote; D018451:Homosexuality, Male; D006720:Homozygote; D006801:Humans; D008297:Male; D008561:Membrane Fusion; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D044469:Racial Groups / Q000235:genetics; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000235:genetics* / Q000502:physiology; D015728:Receptors, HIV / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors
chemical_list: D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV