Parallel evolution of CCR5-null phenotypes in humans and in a natural host of simian immunodeficiency virus.
The C-C chemokine receptor CCR5 in humans and rhesus macaques (Macaca mulatta) serves as the primary coreceptor for cellular entry by macrophagetropic strains of human immunodeficiency virus type 1 (HIV-1) and all reported strains of simian immunodeficiency virus (SIV) [1-6]. Humans homozygous for a 32 bp deletion allele of CCR5, resulting in a null phenotype, are highly resistant to infection by HIV-1 [7-9], prompting development of therapies and vaccines targeting CCR5. We now report a novel deletion allele of CCR5, with an allele frequency of 0.04, in sooty mangabey monkeys (Cercocebus torquatus atys), a natural host of SIV (SIVsmm) [10]. The mutant protein was not expressed at the cell surface and accordingly did not function as a viral coreceptor. Primary activated lymphocytes from mangabeys heterozygous for the deletion allele expressed significantly less CCR5 on the cell surface. Moreover, SIV seroprevalence and viremia were comparable among CCR5 heterozygotes and wild-type animals. Parallel evolution of CCR5-null alleles in humans and sooty mangabeys suggests that similar negative selection pressures have acted against CCR5, as would occur during epidemics of infectious agents that require CCR5 for pathogenesis. Sooty mangabeys bred to homozygosity for the deletion allele will be useful for experimental studies on the context-dependent role of CCR5 in host defense and microbial pathogenesis.
Gladstone Institute of Virology and Immunology San Francisco, California, USA.
E
E
Palacios
L
L
Digilio
H M
HM
McClure
Z
Z
Chen
P A
PA
Marx
M A
MA
Goldsmith
R M
RM
Grant
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology; D019556:COS Cells; D016664:Cercocebus; D006580:Genetic Carrier Screening; D015497:HIV-1 / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D008253:Macaca mulatta; D010641:Phenotype; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014162:Transfection
D015703:Antigens, CD; D015704:CD4 Antigens; D019713:Receptors, CCR5; D011994:Recombinant Proteins