Uncoupling coreceptor usage of human immunodeficiency virus type 1 (HIV-1) from macrophage tropism reveals biological properties of CCR5-restricted HIV-1 isolates from patients with acquired immunodeficiency syndrome

Lachlan Gray, Jasminka Sterjovski, Melissa Churchill, Philip Ellery, Najla Nasr, Sharon R. Lewin, Suzanne M. Crowe, Steven L. Wesselingh, Anthony L. Cunningham, Paul R. Gorry

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99 Citations (Scopus)

Abstract

The mechanisms underlying the pathogenicity of CCR5-restricted (R5) human immunodeficiency virus type-1 (HIV-1) strains are incompletely understood. Acquisition or enhancement of macrophage (M)-tropism by R5 viruses contributes to R5 HIV-1 pathogenesis. In this study, we show that M-tropic R5 viruses isolated from individuals with acquired immunodeficiency syndrome (late R5 viruses) require lower levels of CD4/CCR5 expression for entry, have decreased sensitivity to inhibition by the entry inhibitors TAK-779 and T-20, and have increased sensitivity to neutralization by the Env MAb IgG1b12 compared with non-M-tropic R5 viruses isolated from asymptomatic, immunocompetent individuals (early R5 viruses). Augmenting CCR5 expression levels on monocyte-derived macrophages via retroviral transduction led to a complete or marginal restoration of M-tropism by early R5 viruses, depending on the viral strain. Thus, reduced CD4/CCR5 dependence is a phenotype of R5 HIV-1 associated with M-tropism and late stage infection, which may affect the efficacy of HIV-1 entry inhibitors.

Original languageEnglish
Pages (from-to)384-398
Number of pages15
JournalVirology
Volume337
Issue number2
DOIs
Publication statusPublished or Issued - 5 Jul 2005
Externally publishedYes

Keywords

  • CCR5
  • HIV-1
  • Inhibition
  • Macrophage
  • Neutralization
  • Sensitivity
  • T-20
  • TAK-779
  • Tropism

ASJC Scopus subject areas

  • Virology

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