Abstract
HIV-1 Vpu acts positively on viral infectivity by mediating CD4 degradation in endoplasmic reticulum and enhances virion release by counteracting a virion release restriction factor, tetherin. In order to define the impact of Vpu activity on HIV-1 replication, we have generated a series of site-specific proviral vpu mutants. Of fifteen mutants examined, seven exhibited a replication-defect similar to that of a vpu-deletion mutant in a lymphocyte cell line H9. These mutations clustered in narrow regions within transmembrane domain (TMD) and cytoplasmic domain (CTD). Replication-defective mutants displayed the reduced ability to enhance virion release from a monolayer cell line HEp2 without exception. Upon transfection with Vpu expression vectors, neither TMD mutants nor CTD mutants blocked CD4 expression at the cell surface in another monolayer cell line MAGI. While TMD mutants were unable to down-modulate cell surface tetherin in HEp2 cells, CTD mutants did quite efficiently. Confocal microscopy analysis revealed the difference of intracellular localization between TMD and CTD mutants. In total, replication capability of HIV-1 carrying vpu mutations correlates well with the ability of Vpu to enhance virion release and to impede the cell surface expression of CD4 but not with the ability to down-modulate cell surface tetherin. Our results here suggest that efficient viral replication requires not only down-regulation of cell surface tetherin but also its degradation.
Highlights
Accessory protein Vpu is encoded only by HIV-1 and certain strains of simian immunodeficiency virus (Desrosiers, 2007; Kirchhoff, 2009)
Work proposed that two separable biological activities are directed by distinct Vpu domains: transmembrane domain (TMD) is important for virion release enhancement and cytoplasmic domain (CTD), especially serine 52 and 56, is critical for CD4 degradation (Schubert and Strebel, 1994; Schubert et al, 1996)
The correlation between the viral replication and the two Vpu functions has been examined for a limited number and kind of vpu mutants (Terwilliger et al, 1989; Schubert et al, 1996; Van Damme et al, 2008; Dubé et al, 2010)
Summary
Accessory protein Vpu is encoded only by HIV-1 and certain strains of simian immunodeficiency virus (Desrosiers, 2007; Kirchhoff, 2009). Major functions of HIV-1 Vpu are: (1) to give a positive effect on viral infectivity by mediating CD4 degradation in endoplasmic reticulum (ER) (Bour and Strebel, 2003; Levesque et al, 2003; Tanaka et al, 2003), and (2) to enhance virion release in a cell-type dependent manner by counteracting a host restriction factor, tetherin (Strebel et al, 1989; Terwilliger et al, 1989; Sakai et al, 1995; Neil et al, 2008; Van Damme et al, 2008). Functional mapping of Vpu and its effect on HIV-1 replication have not been well studied
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