CCR5 CORECEPTOR USAGE OF NON-SYNCYTIUM-INDUCING PRIMARY HIV-1 IS INDEPENDENT OF PHYLOGENETICALLY DISTINCT GLOBAL HIV-1 ISOLATES - DELINEATION OF CONSENSUS MOTIF IN THE V3 DOMAIN THAT PREDICTS CCR-5 USAGE
Lh. Xiao et al., CCR5 CORECEPTOR USAGE OF NON-SYNCYTIUM-INDUCING PRIMARY HIV-1 IS INDEPENDENT OF PHYLOGENETICALLY DISTINCT GLOBAL HIV-1 ISOLATES - DELINEATION OF CONSENSUS MOTIF IN THE V3 DOMAIN THAT PREDICTS CCR-5 USAGE, Virology, 240(1), 1998, pp. 83-92
The cellular tropism of human immunodeficiency virus type 1 (HIV-1) is
dependent on utilization of specific chemokine co-receptor: macrophag
e-tropic/non-syncytium-inducing (NSI) viruses use CCR5, whereas T-cell
tropic/syncytium-inducing (SI) viruses preferentially use CXCR4. We h
ave analyzed co-receptor usage of 24 phylogenetically distinct primary
HIV-1 isolates representing group M (clades A-F) and group O with kno
wn SI and NSI phenotype, using lymphocytes from donor with nonfunction
al CCR5 (CCR5(-/-); homozygous 32-bp deletion). While all SI isolates
infected CCR5(-/-) lymphocytes (and hence do not require CCR5 for vira
l entry), all NSI isolates, regardless of clade, did not infect CCR5(-
/-) lymphocytes. Thus, CCR5 expression is required for infection with
NSI isolates and the CCR5 usage is independent of viral genotype. To l
ocalize the viral determinant involved in CCR5 binding, the V3 sequenc
es across the clades were aligned based on the CCR5 usage. There were
conserved uncharged residues at position 11 of V3 (mostly serine/glyci
ne) and negatively charged residues at residue 25 (mostly glutamic/asp
artic acid) among all isolates that used CCR5, whereas substitution wi
th arginine or glutamine at these two positions led to usage of a cc-r
eceptor other than CCR5. This analysis led us to identity a consensus
motif S/GXXXGPGXXXXXXXE/D within the V3 loop that predicts CCR5 cc-rec
eptor usage. Most isolates, with exception of one isolate, containing
the conserved motif and predicted to utilize CCR5 indeed had an absolu
te requirement of CCR5 expression for infectibility. Site-directed mut
agenesis in the infectious molecular clone further confirmed these res
ults. Taken together, these data provide evidence that sequences withi
n the V3 loop provide important residues that might be directly or ind
irectly involved in binding to a CCR5 co-receptor. (C) 1998 Academic P
ress.