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.
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.
Gray
Lachlan
L
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.
Sterjovski
Jasminka
J
Churchill
Melissa
M
Ellery
Philip
P
Nasr
Najla
N
Lewin
Sharon R
SR
Crowe
Suzanne M
SM
Wesselingh
Steven L
SL
Cunningham
Anthony L
AL
Gorry
Paul R
PR
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology*; D015703:Antigens, CD / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D007668:Kidney; D008264:Macrophages / Q000502:physiology* / Q000821:virology; D009000:Monocytes / Q000166:cytology / Q000821:virology; D019713:Receptors, CCR5 / Q000502:physiology*; D015728:Receptors, HIV / Q000502:physiology*
D015703:Antigens, CD; D015704:CD4 Antigens; D019713:Receptors, CCR5; D015728:Receptors, HIV