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 |
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Authors: | Gray Lachlan Sterjovski Jasminka Churchill Melissa Ellery Philip Nasr Najla Lewin Sharon R Crowe Suzanne M Wesselingh Steven L Cunningham Anthony L Gorry Paul R |
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Affiliation: | Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, 3001 Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia. |
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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. |
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Keywords: | HIV-1 CCR5 Macrophage Tropism TAK-779 T-20 Inhibition Neutralization Sensitivity |
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