Structural basis for coreceptor selectivity by the HIV type 1 V3 loop

Timothy Cardozo, Tetsuya Kimura, Sean Philpott, Barbara Weiser, Harold Burger, Susan Zolla-Pazner

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the β2-β3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. TMs V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was im-proved over using only the charge of residues 11 and 25. Thus, the data suggest a new "11/24/25 rule": a pos-itively charged amino acid at position 11, 24, or 25 defines X4; otherwise RS. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R6. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.

Original languageEnglish (US)
Pages (from-to)415-426
Number of pages12
JournalAIDS Research and Human Retroviruses
Volume23
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

Fingerprint

HIV-1
Viruses
Tropism
Chemokine Receptors
Amino Acids
Viral Tropism
CCR5 Receptors
CXC Chemokines
AIDS Vaccines
CC Chemokines
Virus Internalization
Membrane Fusion
Membrane Glycoproteins
Cell Surface Receptors
Crowns
Disease Progression
Macrophages
Lymphocytes
Ligands
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Structural basis for coreceptor selectivity by the HIV type 1 V3 loop. / Cardozo, Timothy; Kimura, Tetsuya; Philpott, Sean; Weiser, Barbara; Burger, Harold; Zolla-Pazner, Susan.

In: AIDS Research and Human Retroviruses, Vol. 23, No. 3, 03.2007, p. 415-426.

Research output: Contribution to journalArticle

Cardozo, Timothy ; Kimura, Tetsuya ; Philpott, Sean ; Weiser, Barbara ; Burger, Harold ; Zolla-Pazner, Susan. / Structural basis for coreceptor selectivity by the HIV type 1 V3 loop. In: AIDS Research and Human Retroviruses. 2007 ; Vol. 23, No. 3. pp. 415-426.
@article{8fa3806041614dfc9509e1400f49df98,
title = "Structural basis for coreceptor selectivity by the HIV type 1 V3 loop",
abstract = "The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by {"}X4-tropic{"} and {"}R5-tropic{"} viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the β2-β3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged {"}patch{"} on the surface of V3 that correlates with coreceptor usage. TMs V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was im-proved over using only the charge of residues 11 and 25. Thus, the data suggest a new {"}11/24/25 rule{"}: a pos-itively charged amino acid at position 11, 24, or 25 defines X4; otherwise RS. This rule gave an overall predictive value of 94{\%} for 217 viruses whose tropism had been determined experimentally as either X4 or R6. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.",
author = "Timothy Cardozo and Tetsuya Kimura and Sean Philpott and Barbara Weiser and Harold Burger and Susan Zolla-Pazner",
year = "2007",
month = "3",
doi = "10.1089/aid.2006.0130",
language = "English (US)",
volume = "23",
pages = "415--426",
journal = "AIDS Research and Human Retroviruses",
issn = "0889-2229",
publisher = "Mary Ann Liebert Inc.",
number = "3",

}

TY - JOUR

T1 - Structural basis for coreceptor selectivity by the HIV type 1 V3 loop

AU - Cardozo, Timothy

AU - Kimura, Tetsuya

AU - Philpott, Sean

AU - Weiser, Barbara

AU - Burger, Harold

AU - Zolla-Pazner, Susan

PY - 2007/3

Y1 - 2007/3

N2 - The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the β2-β3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. TMs V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was im-proved over using only the charge of residues 11 and 25. Thus, the data suggest a new "11/24/25 rule": a pos-itively charged amino acid at position 11, 24, or 25 defines X4; otherwise RS. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R6. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.

AB - The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the β2-β3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. TMs V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was im-proved over using only the charge of residues 11 and 25. Thus, the data suggest a new "11/24/25 rule": a pos-itively charged amino acid at position 11, 24, or 25 defines X4; otherwise RS. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R6. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.

UR - http://www.scopus.com/inward/record.url?scp=34247214426&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247214426&partnerID=8YFLogxK

U2 - 10.1089/aid.2006.0130

DO - 10.1089/aid.2006.0130

M3 - Article

C2 - 17411375

AN - SCOPUS:34247214426

VL - 23

SP - 415

EP - 426

JO - AIDS Research and Human Retroviruses

JF - AIDS Research and Human Retroviruses

SN - 0889-2229

IS - 3

ER -