A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian–human immunodeficiency virus (SHIVKU-1bMC33) susceptible to rimantadine

Hout, David R.; Gomez, Lisa M.; Pacyniak, Erik; Miller, Jean-Marie; Hill, M.; Stephens, Edward B.

doi:10.1016/j.virol.2005.12.025

Cited by 34 publications

(32 citation statements)

References 47 publications

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“…Since scrambling the TM domain blocks both ion channel activity and efficient virus release, it was thought that these activities were related (10,57). Indeed, amiloride-based drugs that block Vpu channel function have been shown to display antiviral activity against HIV-1 in (tetherin-positive) macrophages (9), and other studies report that chimeric Vpu proteins bearing the TM domain of the influenza A virus proton channel M2 were functional for virus release and sensitive to rimantadine (19,20). However, since we found that mutation of S23, known to be required for channel activity (60) and the potential target for amilorides (26), had no effect on tetherin inactivation in our assays, there appears to be a discrepancy in directly correlating cation transport and virus release (tetherin antagonism).…”

Section: Discussionmentioning

confidence: 99%

Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein

Vigan

Neil

2010

J Virol

118

182

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Tetherin (BST2/CD317) potently restricts the particle release of human immunodeficiency virus type 1 (HIV-1) mutants defective in the accessory gene vpu. Vpu antagonizes tetherin activity and induces its cell surface downregulation and degradation in a manner dependent on the transmembrane (TM) domains of both proteins. We have carried out extensive mutagenesis of the HIV-1 NL4.3 Vpu TM domain to identify three amino acid positions, A14, W22, and, to a lesser extent, A18, that are required for tetherin antagonism. Despite the mutants localizing indistinguishably from the wild-type (wt) protein and maintaining the ability to multimerize, mutation of these positions rendered Vpu incapable of coimmunoprecipitating tetherin or mediating its cell surface downregulation. Interestingly, these amino acid positions are predicted to form one face of the Vpu transmembrane alpha helix and therefore potentially contribute to an interacting surface with the transmembrane domain of tetherin either directly or by modulating the conformation of Vpu oligomers. While the equivalent of W22 is invariant in HIV-1/SIVcpz Vpu proteins, the positions of A14 and A18 are highly conserved among Vpu alleles from HIV-1 groups M and N, but not those from group O or SIVcpz that lack human tetherin (huTetherin)-antagonizing activity, suggesting that they may have contributed to the adaption of HIV-1 to human tetherin.Tetherin (CD317/BST2) is an interferon-induced type II membrane glycoprotein of unusual topology (4, 25, 44) that potently restricts the release of diverse mammalian enveloped viral particles from infected cells (24,33,42,45,49,52,63). The protein consists of a short 21-amino-acid cytoplasmic tail, a transmembrane (TM) domain, a predominantly helical extracellular domain containing three cysteine residues that mediate tetherin dimerization (1,44,48) and an extended parallel coiled-coil (18), and a C-terminal glycophosphatidylinositol anchor that links it back to the cellular membrane (25). These structural features are key to the mode of tetherin activity (48). Tetherin is localized to the plasma membrane (PM) and constitutively recycles through intracellular compartments (25,50). It is incorporated into budding virions and acts as a physical tether, cross-linking the virion and cellular membranes, thereby preventing virus particle release from the host cell (11,15,16,48). Strong evidence suggests that the dual membrane anchor of tetherin allows it to form parallel dimers with one terminal in the virion membrane and the other in the cell (48). The result of this is that mature viral particles are retained on cell surfaces by protease-sensitive linkages that contain tetherin, and virions can then be endocytosed and accumulate in endosomal compartments (41,42,48). This relatively nonspe-

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Section: Discussionmentioning

confidence: 99%

Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein

Vigan

Neil

2010

J Virol

118

182

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“…If one compares the sequence of the Vpu and M2 TMDs, the subtype B Vpu contains the sequence Ala-X-X-X-Trp in approximately the same position as M2 with the tryptophan being invariant in Vpu [50]. We subsequently showed that substitution of the alanine in this motif with a histidine residue resulted in a SHIV (SHIV VpuA19H ) that became more sensitive to rimantadine than the SHIV M2 virus [35]. These results indicate that a single amino acid substitution within the TMD of the Vpu protein converts a rimantadine-resistant SHIV to a rimantadine-sensitive SHIV.…”

Section: Is Vpu An Ion Channel Protein?mentioning

confidence: 99%

“…SIV cpz CAM13, SIV cpz ANT, and SIV cpz TAN1 only contain a single casein kinase II site. All four vpu isolates were fused in frame to the gene for enhanced green fluorescence protein (EGFP) and expressed under the control of a CMV promoter, similar to the HIV-1 subtype B vpu genes our laboratory has previously analyzed [34, 35, 74]. All four SIV cpz Vpu fusion proteins were membrane-associated, partially co-localized with DsRed-ER and ECFP-Golgi marker proteins, and completely co-localized with an ECFP-Membrane marker.…”

Section: The Cd4 Down-modulation Function Is Conserved In Vpu Proteinmentioning

confidence: 99%

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

Ruiz

Stephens

2010

CHR

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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.

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“…Park et al [27] determined the three-dimensional structure of the channel-forming trans-membrane domain (VpuTM). Substitution of alanine at position 18 by a histidine (A18H) has been shown to render HIV-1 infections susceptible to rimantadine [28]. The structure of A18H VpuTM was determined, and compared to that of wild-type Vpu TM [29].…”

Section: Vpu From Hiv-1mentioning

confidence: 99%

Relating structure and function of viral membrane-spanning miniproteins

Opella

2015

Current Opinion in Virology

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Many viruses express small hydrophobic membrane proteins. These proteins are often referred to as viroporins because they exhibit ion channel activity. However, the channel activity has not been definitively associated with a biological function in all cases. More generally, protein-protein and protein-phospholipid interactions have been associated with specific biological activities of these proteins. As research has progressed there is a decreased emphasis on potential roles of the channel activity, and increased research on multiple other biological functions. This being the case, it may be more appropriate to refer to them as “viral membrane-spanning miniproteins”. Structural studies are illustrated with Vpu from HIV-1 and p7 from HCV.

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A single amino acid substitution within the transmembrane domain of the human immunodeficiency virus type 1 Vpu protein renders simian–human immunodeficiency virus (SHIVKU-1bMC33) susceptible to rimantadine

Cited by 34 publications

References 47 publications

Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein

Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein

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

Relating structure and function of viral membrane-spanning miniproteins

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