Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5.
CCR5 is one of the primary coreceptors for Env-mediated fusion between cells and human immunodeficiency virus type 1 (HIV-1). Analyses of CCR5 variants in cohorts of HIV-1 high-risk individuals led to the identification of multiple single amino-acid substitutions, which may have functional consequences. This study focused on eight naturally occurring allelic variants located between amino-acid residues 60 and 334 of CCR5. All studied allelic variants were highly expressed on the cell surface of HEK-293 cells and permissive for HIV-1 infection. Variant G301V showed 3.5-fold increase in 50% effective concentration (EC(50)) for CCL4 (MIP 1beta) in a competitive binding assay. There was also a significant reduction in CCL5 (RANTES) EC(50) for the R223Q, A335V and Y339F variants. The most unexpected functional abnormality was exhibited by the R60S variant that exhibited a loss of ligand-induced desensitization in chemotaxis assays, but showed normal CCL4 and CCL5 binding avidity. This mutation is located in the first intracellular loop, a domain that has not previously been shown to be involved in receptor desensitization. In conclusion, our results support earlier studies showing that these naturally occurring point mutations do not limit HIV-1 infection, and indicated that single amino-acid changes can have unexpected functional consequences.
Dong
H-F
HF
Basic Research Program, SAIC Frederick, MD 21702, USA.
Wigmore
K
K
Carrington
M N
MN
Dean
M
M
Turpin
J A
JA
Howard
O M Z
OM
D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020013:Calcium Signaling; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology*; D019742:Chemokines, CC; D002633:Chemotaxis / Q000187:drug effects; D014644:Genetic Variation; D015497:HIV-1; D006801:Humans; D008024:Ligands; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism
C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5