The Vpu Protein: New Concepts in Virus Release and CD4 Down-Modulation

Abstract

Human immunodeficiency virus type 1 (HIV-1) and several simian immunodeficiency viruses (SIV) encode for a transmembrane protein known as Vpu. While the smallest of the HIV-1 proteins, it has two important functions within virus-infected cells. The first of these functions is the down-regulation of the CD4 receptor to prevent its interaction with the HIV-1 envelope glycoprotein. Vpu interacts with the CD4 receptor in the rough endoplasmic reticulum (RER), resulting in its re-translocation across the RER and subsequent degradation via the proteasomal pathway. The second major function of the Vpu protein is to facilitate release of virus from infected cells. Previous studies have shown that virus release is cell type specific, suggesting that certain cells may express a restriction factor that inhibits virus release in the absence of Vpu. Recently, bone marrow stromal antigen 2 (BST-2/HM124/CD317/tetherin) has been identified as this factor. This review will focus on new findings within the last four years on the role of Vpu in CD4 down-regulation and the restriction of virus release from cells. We will relate these findings to virus pathogenesis and propose questions regarding BST-2 as a restriction factor.

Membrane raft association of the Vpu protein of human immunodeficiency virus type 1 correlates with enhanced virus release

“…The derivation and pathogenicity of SHIV KU-1bMC33 and no vpu SHIV KU-1bMC33 have been described (McCormick-Davis et al, 2000; Singh et al, 2003; Stephens et al, 2002). The derivation of the SHIV KU-2MC4 Δvpu plasmid has been described (Ruiz et al, 2010). Vectors expressing the subtype B (pc vpuegfp ) and C Vpu (pcv pu sc egfp1 ) proteins fused to enhanced green fluorescent protein (eGFP) and the Vpu TM EGFP (pcv pu TM egfp ) mutant have been previously described (Singh et al , 2003; Gomez et al , 2005; Pacyniak et al , 2005; Ruiz et al, 2008).…”

“…Viral protein U (Vpu) encoded by human immunodeficiency virus type I (HIV-1) augments viral pathogenesis by down-modulating CD4 molecules from the surface of infected cells and enhancing virion release (Fujita et al, 1997; Klimkait et al, 1990; reviewed in Ruiz et al, 2010; Schubert et al, 1998). Membrane association is critical for both activities although an earlier study indicated that the primary structure of the transmembrane domain was irrelevant for CD4 down-modulation (Schubert et al, 1996).…”

Sites of Action of HIV-1 Vpu in BST-2/Tetherin Downregulation

“…Vpu mediates the degradation of CD4 receptors [24,25] and enhances the release of progeny virions from virus-producer cells [26][27][28][29][30] by antagonizing the restriction to viral egress imposed by BST-2 [3,4,31]. Furthermore, counteraction of BST-2 by Vpu is important for HIV-1 pathogenesis in vivo [32][33][34], indicating that BST-2 is a functionally active restriction factor whose antagonism is required for the establishment of a successful infection in vivo.…”

Transmembrane Domain Determinants of CD4 Downregulation by HIV-1 Vpu

“…Once inside the cell, the genetic material of the virus directs rapid and sustained downregulation of CD4 (26, 62), a phenomenon that promotes viral spread by preventing superinfection, enabling the release of progeny virions, and interfering with the host immune response (3,6,34,53). The ability of HIV-1 to downregulate CD4 depends on two accessory proteins encoded in the viral genome, Nef and Vpu (32,38,45,61). Nef is a myristoylated protein that attaches to the cytosolic leaflet of the plasma membrane, where it functions to link the cytosolic tail of CD4 to the clathrinassociated adaptor protein 2 (AP-2) complex (1,12,16,17,19,24,39).…”