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Characterization of human immunodefi...

Suphaphiphat, Pirada.

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Characterization of human immunodeficiency virus type 1gp120 interaction with the CCR5 chemokine coreceptor.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Characterization of human immunodeficiency virus type 1gp120 interaction with the CCR5 chemokine coreceptor./
Author:	Suphaphiphat, Pirada.
Description:	198 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-05, Section: B, page: 2382.
Contained By:	Dissertation Abstracts International67-05B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3217893
ISBN:	9780542694097

Characterization of human immunodeficiency virus type 1gp120 interaction with the CCR5 chemokine coreceptor.
Suphaphiphat, Pirada.

Characterization of human immunodeficiency virus type 1gp120 interaction with the CCR5 chemokine coreceptor. - 198 p.

Source: Dissertation Abstracts International, Volume: 67-05, Section: B, page: 2382.

Thesis (Ph.D.)--Harvard University, 2006.

Entry of human immunodeficiency virus type 1 (HIV-1) into target cells generally requires sequential interaction between the virus envelope glycoprotein gp120, the CD4 receptor, and a chemokine coreceptor. Based on studies on HIV-1 subtype B, the ability of a given virus strain to use CCR5 as a coreceptor is governed largely by the third variable (V3) loop and the well-conserved bridging sheet domain in gp120. Whether corresponding gp120 regions in other HIV-1 subtypes determine such viral characteristics has not been adequately addressed. Therefore, we sought to determine whether the current model for gp120-CCR5 interaction is relevant to non-subtype B HIV-1 and to define precise gp120 determinants involved in CCR5 utilization by these viruses. We conducted alanine-scanning mutagenesis of the V3 loop and of selected amino acids in the fourth conserved (C4) region of genetically divergent viruses and characterized the resulting mutants for CCR5-dependent membrane fusion and viral entry. Our cross-comparison analysis revealed that CCR5 usage mediated by HIV-1 envelopes of subtypes C, E, and B involved several overlapping residues in the stem region of the V3 loop, suggesting that the importance of the V3 stem in CCR5 utilization may be conserved across subtypes. In contrast, the contribution of V3 crown residues in fusion and viral entry appeared to vary by subtype or isolate, possibly due to differences in V3 loop conformation. We also provided evidence to support the notion that residues in V3 and C4 may play different roles in the binding and fusion steps of gp120-CCR5 interaction. In subtype B gp120, mutations in the V3 stem disrupted both CCR5 binding of gp120 subunits and subsequent membrane fusion, whereas mutations in the V3 crown and C4 residues had much more impact on CCR5 binding than on fusion activity. Our results indicated that CCR5 binding by monomeric gp120 is not a reliable predictor of CCR5 utilization by gp120 when it is presented as a trimeric form. Characterizing the interaction of gp120 and CCR5 can help elucidate the genetic basis of functional convergence in CCR5 utilization by genetically divergent HIV-1 and may provide new opportunities for the development of inhibitors of viral entry.

ISBN: 9780542694097Subjects--Topical Terms:

1017719
Biology, Molecular.

Characterization of human immunodeficiency virus type 1gp120 interaction with the CCR5 chemokine coreceptor.
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520 $a Entry of human immunodeficiency virus type 1 (HIV-1) into target cells generally requires sequential interaction between the virus envelope glycoprotein gp120, the CD4 receptor, and a chemokine coreceptor. Based on studies on HIV-1 subtype B, the ability of a given virus strain to use CCR5 as a coreceptor is governed largely by the third variable (V3) loop and the well-conserved bridging sheet domain in gp120. Whether corresponding gp120 regions in other HIV-1 subtypes determine such viral characteristics has not been adequately addressed. Therefore, we sought to determine whether the current model for gp120-CCR5 interaction is relevant to non-subtype B HIV-1 and to define precise gp120 determinants involved in CCR5 utilization by these viruses. We conducted alanine-scanning mutagenesis of the V3 loop and of selected amino acids in the fourth conserved (C4) region of genetically divergent viruses and characterized the resulting mutants for CCR5-dependent membrane fusion and viral entry. Our cross-comparison analysis revealed that CCR5 usage mediated by HIV-1 envelopes of subtypes C, E, and B involved several overlapping residues in the stem region of the V3 loop, suggesting that the importance of the V3 stem in CCR5 utilization may be conserved across subtypes. In contrast, the contribution of V3 crown residues in fusion and viral entry appeared to vary by subtype or isolate, possibly due to differences in V3 loop conformation. We also provided evidence to support the notion that residues in V3 and C4 may play different roles in the binding and fusion steps of gp120-CCR5 interaction. In subtype B gp120, mutations in the V3 stem disrupted both CCR5 binding of gp120 subunits and subsequent membrane fusion, whereas mutations in the V3 crown and C4 residues had much more impact on CCR5 binding than on fusion activity. Our results indicated that CCR5 binding by monomeric gp120 is not a reliable predictor of CCR5 utilization by gp120 when it is presented as a trimeric form. Characterizing the interaction of gp120 and CCR5 can help elucidate the genetic basis of functional convergence in CCR5 utilization by genetically divergent HIV-1 and may provide new opportunities for the development of inhibitors of viral entry.
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