South African mutations of the CCR5 coreceptor for HIV modify interaction with chemokines and HIV Envelope protein.
The CCR5 chemokine receptor is the major coreceptor for HIV-1 and the receptor for CC-chemokines, MIP-1alpha, MIP-1beta, and regulated upon activation normal T-cell-expressed and secreted. Individuals, who are homozygous for the nonfunctional CCR5Delta32 allele, are largely resistant to HIV-1 infection. Four unique mutations that affect the amino acid sequence of CCR5 have been identified in South Africa. We have assessed the effect of these mutations on CCR5 interactions with chemokines and HIV Envelope protein. The LeuPhe mutation did not affect CCR5 expression, chemokine binding, intracellular signaling, or interaction with Envelope. The ArgGln mutant was similar to wild-type CCR5, but ligand-independent intracellular signaling suggests that it is partially constitutively active. The AspVal mutation decreased chemokine-binding affinity, chemokine-stimulated intracellular signaling, and receptor expression. It also decreased HIV Envelope-mediated cell fusion. The ArgStop mutant showed no measurable chemokine binding or signaling and no measurable expression of CCR5 at the cell surface or within the cell. Consistent with lack of cell surface expression, it did not support envelope-mediated cell fusion. These results show that South African CCR5 variants have a range of phenotypes in vitro that may reflect altered chemokine responses and susceptibility to HIV infection in individuals who carry these alleles.
Folefoc
Asongna T
AT
University of Cape Town/Medical Research Council Research Group for Receptor Biology, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town Faculty of Health Sciences, Observatory, Cape Town, South Africa.
Fromme
Bernhard J
BJ
Katz
Arieh A
AA
Flanagan
Colleen A
CA
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002459:Cell Fusion; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D016373:DNA, Antisense / Q000235:genetics; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000235:genetics; D006678:HIV / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000502:physiology; D009154:Mutation; D016133:Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000235:genetics*; D013019:South Africa; D014162:Transfection; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D017931:DNA Primers; D016373:DNA, Antisense; D015683:Gene Products, gag; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; D004247:DNA