Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1

Shawn E. Kuhmann, Emily J. Platt, Susan L. Kozak, David Kabat

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

In addition to the primary cell surface receptor CD4, CCR5 or another coreceptor is necessary for infections by human immunodeficiency virus type 1 (HIV-1), yet the mechanisms of coreceptor function and their stoichiometries in the infection pathway remain substantially unknown. To address these issues, we studied the effects of CCR5 concentrations on HIV-1 infections using wild-type CCR5 and two attenuated mutant CCR5s, one with the mutation Y14N at a critical tyrosine sulfation site in the amino terminus and one with the mutation G163R in extracellular loop 2. The Y14N mutation converted a YYT sequence at positions 14 to 16 to an NYT consensus site for N-linked glycosylation, and the mutant protein was shown to be glycosylated at that position. The relationships between HIV-1 infectivity values and CCR5 concentrations took the form of sigmoidal (S-shaped) curves, which were dramatically altered in different ways by these mutations. Both mutations shifted the curves by factors of approximately 30- to 150-fold along the CCR5 concentration axis, consistent with evidence that they reduce affinities of virus for the coreceptor. In addition, the Y14N mutation specifically reduced the maximum efficiencies of infection that could be obtained at saturating CCR5 concentrations. The sigmoidal curves for all R5 HIV-1 isolates were quantitatively consistent with a simple mathematical model, implying that CCR5s reversibly associate with cell surface HIV-1 in a concentration- dependent manner, that approximately four to six CCR5s assemble around the virus to form a complex needed for infection, and that both mutations inhibit assembly of this complex but only the Y14N mutation also significantly reduces its ability to successfully mediate HIV-1 infections. Although several alternative models would be compatible with our data, a common feature of these alternatives is the cooperation of multiple CCR5s in the HIV-1 infection pathway. This cooperativity will need to be considered in future studies to address in detail the mechanism of CCR5-mediated HIV-1 membrane fusion.

Original languageEnglish (US)
Pages (from-to)7005-7015
Number of pages11
JournalJournal of Virology
Volume74
Issue number15
DOIs
StatePublished - Aug 2000

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Human immunodeficiency virus 1
HIV-1
mutation
Mutation
Infection
infection
Virus Diseases
Viruses
Virus Internalization
viruses
mutants
Cell Surface Receptors
stoichiometry
Mutant Proteins
glycosylation
Glycosylation
Tyrosine
tyrosine
Theoretical Models
mathematical models

ASJC Scopus subject areas

  • Immunology

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Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1. / Kuhmann, Shawn E.; Platt, Emily J.; Kozak, Susan L.; Kabat, David.

In: Journal of Virology, Vol. 74, No. 15, 08.2000, p. 7005-7015.

Research output: Contribution to journalArticle

Kuhmann, Shawn E. ; Platt, Emily J. ; Kozak, Susan L. ; Kabat, David. / Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1. In: Journal of Virology. 2000 ; Vol. 74, No. 15. pp. 7005-7015.
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