Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.
HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref.1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains, and the orphan receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains). Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1 infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major co-receptor for primary HIV-1 strains. The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.
Samson
M
M
IRIBHN and Services de Genetique Medicale, Virologie and Immunodeficiences, Universite Libre de Bruxelles, Belgium.
Libert
F
F
Doranz
B J
BJ
Rucker
J
J
Liesnard
C
C
Farber
C M
CM
Saragosti
S
S
Lapoumeroulie
C
C
Cognaux
J
J
Forceille
C
C
Muyldermans
G
G
Verhofstede
C
C
Burtonboy
G
G
Georges
M
M
Imai
T
T
Rana
S
S
Yi
Y
Y
Smyth
R J
RJ
Collman
R G
RG
Doms
R W
RW
Vassart
G
G
Parmentier
M
M
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D015331:Cohort Studies; D017931:DNA Primers; D016368:Frameshift Mutation; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D006679:HIV Seropositivity / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015728:Receptors, HIV / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D044465:White People / Q000235:genetics
D017931:DNA Primers; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV