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Journal of Virology, November 2000, p. 10229-10235, Vol. 74, No. 21
Department of Medicine, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Received 28 June 2000/Accepted 1 August 2000
Human immunodeficiency virus type 1 (HIV-1) variants that use the
coreceptor CCR5 for entry (R5; macrophage tropic) predominate in early infection, while variants that use CXCR4 emerge during disease
progression. Some late-stage variants use CXCR4 alone (X4; T-cell
tropic), while others use both CXCR4 and CCR5 (R5X4; dualtropic).
It has been proposed that dualtropic R5X4 strains are intermediates in
the evolution from R5 to X4, and we hypothesized that a dualtropic
primary-isolate quasispecies might contain variants that represent
the spectrum of coreceptor use in vivo. We generated a panel of 35 functional full-length env clones from the primary-isolate quasispecies of a dualtropic prototype strain, HIV-1
89.6PI. Thirty of the functional env clones
(86%) were R5X4, four (11%) were R5, and one (3%) was predominantly
X4. V3 to V5 sequences did not reveal clustering by coreceptor usage,
and no specific sequence motif or V3 charge pattern corresponded to
coreceptor utilization. Complete sequencing of seven functionally
divergent Env proteins revealed
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Heterogeneous Spectrum of Coreceptor Usage among Variants
within a Dualtropic Human Immunodeficiency
Virus Type 1 Primary-Isolate Quasispecies
98.7% homology and conservation of
structurally important domains. Chimeras between the R5X4 89.6 prototype and an R5 variant indicated that multiple regions contributed
to the use of CXCR4, while chimeras with the X4 variant implicated a
single residue in V4 in CCR5 use. These results confirm, at the
molecular level, both that dualtropic variants are a predominant
component of late-stage syncytium-inducing isolates and that variants
restricted to each coreceptor coexist with dualtropic species in vivo.
Coreceptor-restricted minority variants may reflect residual R5 species
from earlier in disease as well as emerging X4 variants.
*
Corresponding author. Mailing address: University of
Pennsylvania School of Medicine, 807 Abramson Building, 34th and Civic Center Blvd., Philadelphia, PA 19104-4399. Phone: (215) 898-0913. Fax:
(215) 573-4446. E-mail: collmanr{at}mail.med.upenn.edu.
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