Exclusive and Persistent Use of the Entry Coreceptor CXCR4 by Human Immunodeficiency Virus Type 1 from a Subject Homozygous for CCR5 Δ32
Nelson L. Michael,Julie A. E. Nelson,Vineet N. KewalRamani,George Chang,Stephen J. O'Brien,John R. Mascola,Barbara Volsky,Mark K. Louder,Gilbert C. White,Dan R. Littman,Ronald Swanstrom,Thomas R. O'Brien +11 more
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It is reported that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and phenotypically syncytium inducing (SI); exclusively uses CXCR4; and replicates well in CCR5−/− primary T cells.Abstract:
Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding both to CD4 (14, 33, 40) and to one of the seven transmembrane G-protein-coupled chemokine receptors recently discovered to act as coreceptors (2, 6, 8, 11, 16, 19, 20, 24, 46). Viruses able to infect cultured T-cell lines (T tropic) are syncytium inducing (SI), are frequently found in late-stage HIV disease, and utilize the chemokine receptor CXCR4; macrophage-tropic (M-tropic) viruses are non-SI (NSI) in T-cell lines, are found throughout disease, and utilize CCR5 (2, 6, 8, 11, 16, 19, 20, 24, 46). Two other chemokine receptors, CCR2B and CCR3, function as minor HIV-1 entry coreceptors (11, 19, 48), with CCR3 likely playing a role in central nervous system HIV-1 infection (27). Recently, two seven-transmembrane receptors with extensive sequence homology to CCR5 and CXCR4—Bonzo (3, 17) and BOB (17, 22)—have been shown to mediate entry of simian immunodeficiency virus (SIV), as well as some M-tropic HIV-1 and HIV-2 strains. Another seven-transmembrane receptor, GPR1, mediates the entry of SIV but not HIV-1 (22). The CC chemokines RANTES, MIP-1α, and MIP-1β are natural ligands for CCR5 (49, 51), and the CXC chemokine stromal-cell-derived factor 1 (SDF-1) is the only known natural ligand for CXCR4 (8, 46, 49, 51). Ligand binding to both receptors is associated with G-protein-coupled signal transduction and leukocyte chemoattraction (8, 46, 49, 51), as well as partial viral-entry antagonism (2, 8, 11–13, 16, 20, 29, 46, 58). Viral entry and signal transduction are separable in vitro functions for CCR5 (4, 23, 26), but the two may be biologically related to viral pathogenesis in vivo.
Most viral isolates recovered during primary and early chronic infection are NSI regardless of the route of infection (56, 59). Evolution of coreceptor use from CCR5 to CXCR4 is coincident with viral phenotypic switch from NSI to SI and progression to AIDS in approximately half of all HIV-1-seropositive subjects (31, 32, 34, 43, 54). A 32-bp inactivating deletion in CCR5 (CCR5 Δ32) common to northern European populations (41) has been associated with delayed disease progression in heterozygotes (15, 18, 21, 28, 43, 50, 60) and especially in those harboring NSI virus (18, 43). Subjects homozygous for CCR5 Δ32 (CCR5 −/−) are at a sharply reduced risk for virus transmission (15, 21, 28, 38, 43, 52, 60). However, reports of HIV-1 infected CCR5 −/− individuals, by our group and others, demonstrate that this risk reduction is finite (5, 7, 47, 55). We now report the viral phenotype, replication kinetics, macrophage tropism, and coreceptor usage of viruses derived early and late in disease from an HIV-1-infected CCR5 −/− subject.read more
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CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease
TL;DR: In this paper, the chemokine receptors CXCR4 and CCR5, members of the G protein-coupled receptor superfamily, have been identified as the principal coreceptors for T cell line-tropic and macrophagetropic HIV-1 isolates, respectively.
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International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors
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TL;DR: A widely accepted receptor nomenclature system is described, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area and updating current concepts of the biology and pharmacology of the chemokine system.
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The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection.
TL;DR: This review will discuss what is known, what is suspected, and what still remains obscure about the central role played by coreceptor expression and usage in the transmission and pathogenic consequences of human immunodeficiency virus type 1 (HIV-1) infection.
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Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection
Craig W. Hendrix,Ann C. Collier,Michael M. Lederman,Dominique Schols,Richard B. Pollard,Stephen J. Brown,J. Brooks Jackson,Robert W. Coombs,Marshall J. Glesby,Charles Flexner,Gary Bridger,Karin Badel,Ronald Trevor Macfarland,Geoffrey W. Henson,Gary Calandra +14 more
TL;DR: Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.
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