gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5

Navid Madani, Susan L. Kozak, Michael P. Kavanaugh, David Kabat

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Signal transductions by the dual-function CXCR4 and CCR5 chemokine receptors/HIV type 1 (HIV-1) coreceptors were electrophysiologically monitored in Xenopus laevis oocytes that also coexpressed the viral receptor CD4 and a G protein-coupled inward-rectifying K+ channel (Kit 3.1). Large Kit 3.1-dependent currents generated in response to the corresponding chemokines (SDF-1α for CXCR4 and MIP-1α; MIP-1β and RANTES for CCR5) were blocked by pertussis toxin, suggesting involvement of inhibitory guanine nucleotide-binding proteins. Prolonged exposures to chemokines caused substantial but incomplete desensitization of responses with time constants of 5-7 min and recovery time constants of 12-19 min. CXCR4 and CCR5 exhibited heterologous desensitization in this oocyte system, suggesting possible inhibition of a common downstream step in their signaling pathways. In contrast to chemokines, perfusion with monomeric or oligomeric preparations of the glycoprotein of M(r) 120,000 (gp120) derived from several isolates of HIV-1 did not activate signaling by CXCR4 or CCR5 regardless of CD4 coexpression. However, adsorption of the gp120 from a T-cell-tropic virus resulted in CD4-dependent antagonism of CXCR4 response to SDF-1α, whereas gp120 from macrophage-tropic viruses caused CD4-dependent antagonism of CCR5 response to MIP-1α. These antagonisms could be partially overcome by high concentrations of chemokines and were specific for coreceptors of the corresponding HIV-1 isolates, suggesting that they resulted from direct interactions of gp120-CD4 complexes with coreceptors and that they did not involve the desensitization pathway. These results indicate that monomeric or oligomeric gp120s specifically antagonize CXCR4 and CCR5 signaling in response to chemokines, but they do not exclude the possibility that gp120s might also function as weak agonists in some cells. The gp120-mediated disruption of CXCR4 and CCR5 signaling may contribute to AIDS pathogenesis.

Original languageEnglish (US)
Pages (from-to)8005-8010
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number14
DOIs
StatePublished - Jul 7 1998

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Chemokines
Glycoproteins
HIV
HIV-1
Oocytes
CCR5 Receptors
Viruses
Chemokine CCL5
CD4 Antigens
Guanine Nucleotides
Chemokine Receptors
Pertussis Toxin
Xenopus laevis
GTP-Binding Proteins
Adsorption
Signal Transduction
Carrier Proteins
Acquired Immunodeficiency Syndrome
Perfusion
Macrophages

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

gp120 envelope glycoproteins of human immunodeficiency viruses competitively antagonize signaling by coreceptors CXCR4 and CCR5. / Madani, Navid; Kozak, Susan L.; Kavanaugh, Michael P.; Kabat, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 14, 07.07.1998, p. 8005-8010.

Research output: Contribution to journalArticle

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