The Antiviral Activities of Tetherin

Neil, Stuart J. D.

doi:10.1007/978-3-642-37765-5_3

Cited by 89 publications

(137 citation statements)

References 167 publications

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“…b-Actin was used as an internal control; primer sequence: 5¢-TTC CTG GGG ATG GAG TC-3¢ (forward); 5¢-CAG GTC TTT GCG GAT GTC-3¢ (reverse). Our data showed that both APOBEC3A/G, and tetherin, potent anti-HIV host factors, 17,[24][25][26] were significantly upregulated in MDMs treated exogenously with NTZ (Fig. 1F), supporting the belief that NTZ may be acting by limiting infection at early and late stages of the viral life cycle.…”

Section: Gekonge Bardin and Montanersupporting

confidence: 69%

“…13,21,22 We analyzed the modulation of two known type I interferon-induced negative regulators of viral replication (ABOBEC 3G and tetherin [23][24][25][26][27][28] ) following 48-h incubation of MDM with 10 lg/ml NTZ. We utilized the following real-time reverse transcriptase polymerase chain reaction (RT-PCR) primers to characterize the expression of IFN-response genes following NTZ exposure, i.e., tetherin, primer sequence: 5¢-AAG AAA GTG GAG GAG CTT GAG G-3¢ (forward); 5¢-CCT GGT TTT CTC TTC TCA GTC G-3¢ (reverse), APOBEC3A, primer sequence: 5¢-TTC TTT GCA GTT GGA CCC GG-3¢ (forward); 5¢-CTC ATC TAG TCC ATC CCA GG-3¢ (reverse), and APOBEC3G, primer sequence: 5¢-TTA CCT GCT TCA CCT CCT GG-3¢ (forward); 5¢-TCA TCT AGT CCA TCC CAG GG-3¢ (reverse).…”

Section: Gekonge Bardin and Montanermentioning

confidence: 99%

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Short Communication: Nitazoxanide Inhibits HIV Viral Replication in Monocyte-Derived Macrophages

Gekonge

Bardin

Montaner

2015

AIDS Research and Human Retroviruses

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We document the anti-HIV activity of nitazoxanide (NTZ), the first member of the thiazolide class of antiinfective drugs, originally effective against enteritis caused by Cryptosporidium parvum and Giardia lamblia. NTZ has been administered extensively worldwide, with no severe toxicities associated with its use. Here, we show for the first time that NTZ decreases HIV-1 replication in monocyte-derived macrophages (MDM) if present before or during HIV-1 infection. This NTZ effect is associated with downregulation of HIV-1 receptors CD4 and CCR5, and increasing gene expression of host cell anti-HIV resistance factors APOBEC3A/3G and tetherin. As NTZ is already in clinical use for other conditions, this newly described anti-HIV activity in MDM may facilitate innovative intensification strategies against HIV-1 when combined with current antiretroviral drug regimens.

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Section: Gekonge Bardin and Montanersupporting

confidence: 69%

Section: Gekonge Bardin and Montanermentioning

confidence: 99%

Short Communication: Nitazoxanide Inhibits HIV Viral Replication in Monocyte-Derived Macrophages

Gekonge

Bardin

Montaner

2015

AIDS Research and Human Retroviruses

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“…The ability of tetherin to engage diverse families of enveloped viruses and the evolution of distinct mechanisms to counteract tetherin suggests that tetherin-mediated restriction does not require specific interactions between tetherin and viral proteins (22). Rather, it is the incorporation of tetherin into the viral and cellular membranes that is important.…”

mentioning

confidence: 99%

“…Each monomer consists of a continuous alpha helix arranged in parallel orientation, forming a coiled-coil dimer 14.5 to 16.5 nm in length (27)(28)(29)(30). Based on X-ray structures of the mammalian ectodomains, researchers have proposed two main models to predict how tetherin cross-links HIV-1 to the plasma membrane (22,31), with evidence to support both (see Fig. S1 in the supplemental material).…”

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confidence: 99%

Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells

Strauss

Hammonds

et al. 2016

J Virol

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Tetherin (BST2, CD317, or HM1.24) is a host cellular restriction factor that prevents the release of enveloped viruses by mechanically linking virions to the plasma membrane. The precise arrangement of tetherin molecules at the plasma membrane site of HIV-1 assembly, budding, and restriction is not well understood. To gain insight into the biophysical mechanism underlying tetherin-mediated restriction of HIV-1, we utilized cryo-electron tomography (cryo-ET) to directly visualize HIV-1 virus-like particles (VLPs) and virions tethered to human cells in three dimensions (3D). Rod-like densities that we refer to as tethers were seen connecting HIV-1 virions to each other and to the plasma membrane. Native immunogold labeling showed tetherin molecules located on HIV-1 VLPs and virions in positions similar to those of the densities observed by cryo-ET. The location of the tethers with respect to the ordered immature Gag lattice or mature conical core was random. However, tethers were not uniformly distributed on the viral membrane but rather formed clusters at sites of contact with the cell or other virions. Chains of tethered HIV-1 virions often were arranged in a linear fashion, primarily as single chains and, to a lesser degree, as branched chains. Distance measurements support the extended tetherin model, in which the coiled-coil ectodomains are oriented perpendicular with respect to the viral and plasma membranes. IMPORTANCETetherin is a cellular factor that restricts HIV-1 release by directly cross-linking the virus to the host cell plasma membrane. We used cryo-electron tomography to visualize HIV-1 tethered to human cells in 3D. We determined that tetherin-restricted HIV-1 virions were physically connected to each other or to the plasma membrane by filamentous tethers that resembled rods ϳ15 nm in length, which is consistent with the extended tetherin model. In addition, we found the position of the tethers to be arbitrary relative to the ordered immature Gag lattice or the mature conical cores. However, when present as multiple copies, the tethers clustered at the interface between virions. Tethered HIV-1 virions were arranged in a linear fashion, with the majority as single chains. This study advances our understanding of tetherin-mediated HIV-1 restriction by defining the spatial arrangement and orientation of tetherin molecules at sites of HIV-1 restriction.

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“…Proteomics studies showed that a large number (ϳ100) of cellular proteins associated with the plasma membrane are incorporated into HIV-1 particles released by infected macrophages (21). However, the specific molecular mechanisms that mediate incorporation of host membrane proteins into virions remain largely unexplored, except for those for BST-2/tetherin (22) and virus receptors (23)(24)(25). This is in contrast to the incorporation of viral glycoproteins, where several mechanisms have been investigated (26,27).…”

mentioning

confidence: 99%

Basic Motifs Target PSGL-1, CD43, and CD44 to Plasma Membrane Sites Where HIV-1 Assembles

Grover

Veatch

Ono

2015

J Virol

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HIV-1 incorporates various host membrane proteins during particle assembly at the plasma membrane; however, the mechanisms mediating this incorporation process remain poorly understood. We previously showed that the HIV-1 structural protein Gag localizes to the uropod, a rear-end structure of polarized T cells, and that assembling Gag copatches with a subset, but not all, of the uropod-directed proteins, i.e., PSGL-1, CD43, and CD44, in nonpolarized T cells. The latter observation suggests the presence of a mechanism promoting virion incorporation of these cellular proteins. To address this possibility and identify molecular determinants, in the present study we examined coclustering between Gag and the transmembrane proteins in T and HeLa cells using quantitative two-color superresolution localization microscopy. Consistent with the findings of the T-cell copatching study, we found that basic residues within the matrix domain of Gag are required for Gag-PSGL-1 coclustering. Notably, the presence of a polybasic sequence in the PSGL-1 cytoplasmic domain significantly enhanced this coclustering. We also found that polybasic motifs present in the cytoplasmic tails of CD43 and CD44 also promote their coclustering with Gag. ICAM-1 and ICAM-3, uropod-directed proteins that do not copatch with Gag in T cells, and CD46, a non-uropod-directed protein, showed no or little coclustering with Gag. However, replacing their cytoplasmic tails with the cytoplasmic tail of PSGL-1 significantly enhanced their coclustering with Gag. Altogether, these results identify a novel mechanism for host membrane protein association with assembling HIV-1 Gag in which polybasic sequences present in the cytoplasmic tails of the membrane proteins and in Gag are the major determinants. IMPORTANCENascent HIV-1 particles incorporate many host plasma membrane proteins during assembly. However, it is largely unknown what mechanisms promote the association of these proteins with virus assembly sites within the plasma membrane. Notably, our previous study showed that HIV-1 structural protein Gag colocalizes with a group of uropod-directed transmembrane proteins, PSGL-1, CD43, and CD44, at the plasma membrane of T cells. The results obtained in the current study using superresolution localization microscopy suggest the presence of a novel molecular mechanism promoting the association of PSGL-1, CD43, and CD44 with assembling HIV-1 which relies on polybasic sequences in HIV-1 Gag and in cytoplasmic domains of the transmembrane proteins. This information advances our understanding of virion incorporation of host plasma membrane proteins, some of which modulate virus spread positively or negatively, and suggests a possible new strategy to enrich HIV-1-based lentiviral vectors with a desired transmembrane protein. HIV-1 assembles at the plasma membrane in most cell types. The viral structural protein Gag, synthesized as a precursor polyprotein (Pr55), initiates and coordinates viral assembly at the plasma membrane. Membrane binding and targeting of ...

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The Antiviral Activities of Tetherin

Cited by 89 publications

References 167 publications

Short Communication: Nitazoxanide Inhibits HIV Viral Replication in Monocyte-Derived Macrophages

Short Communication: Nitazoxanide Inhibits HIV Viral Replication in Monocyte-Derived Macrophages

Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells

Basic Motifs Target PSGL-1, CD43, and CD44 to Plasma Membrane Sites Where HIV-1 Assembles

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