The Pericentriolar Recycling Endosome Plays a Key Role in Vpu‐mediated Enhancement of HIV‐1 Particle Release

Varthakavi, Vasundhara; Smith, Rita M.; Martin, Kenneth L.; Derdowski, Aaron; Lapierre, Lynne A.; Goldenring, James R.; Spearman, Paul

doi:10.1111/j.1600-0854.2005.00380.x

Cited by 92 publications

(82 citation statements)

References 47 publications

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“…Alternatively, rapid Env endocytosis may minimize surface viral antigen exposure to antibodies and perhaps be linked to the maturation of Env precursors to gp120/105 and gp41, which is achieved by furin-like proteases, which themselves recycle between the TGN and the cell surface (28). Since mutation of the GYxx signal in the Rod Env cytoplasmic tail abolishes its ability to relocalize tetherin from the PM, and previous data from the Spearman group demonstrated a requirement for the recycling endosome in Vpu and HIV-2 Env function (47), tetherin trapping in the TGN is likely to occur after removal from the cell surface, but whether HIV-2 Env actively promotes this removal or whether its own trafficking intersects with tetherin in the endosomal/TGN compartments remains to be determined. Furthermore, our obser-vation that the CS-mutant of Env still retains the ability to coimmunoprecipitate with tetherin suggests that this interaction is not sufficient to explain antagonism and sequestration of tetherin.…”

Section: Discussionmentioning

confidence: 96%

Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Tortorec

Neil

2009

J Virol

260

353

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Tetherin (CD317/BST-2), an interferon-induced membrane protein, restricts the release of nascent retroviral particles from infected cell surfaces. While human immunodeficiency virus type 1 (HIV-1) encodes the accessory gene vpu to overcome the action of tetherin, the lineage of primate lentiviruses that gave rise to HIV-2 does not. It has been previously reported that the HIV-2 envelope glycoprotein has a Vpu-like function in promoting virus release. Here we demonstrate that the HIV-2 Rod envelope glycoprotein (HIV-2 Rod Env) is a tetherin antagonist. Expression of HIV-2 Rod Env, but not that of HIV-1 or the closely related simian immunodeficiency virus (SIV) SIVmac1A11, counteracts tetherin-mediated restriction of Vpu-defective HIV-1 in a cell-type-specific manner. This correlates with the ability of the HIV-2 Rod Env to mediate cell surface downregulation of tetherin. Antagonism requires an endocytic motif conserved across HIV/SIV lineages in the gp41 cytoplasmic tail, but specificity for tetherin is governed by extracellular determinants in the mature Env protein. Coimmunoprecipitation studies suggest an interaction between HIV-2 Rod Env and tetherin, but unlike studies with Vpu, we found no evidence of tetherin degradation. In the presence of HIV-2 Rod Env, tetherin localization is restricted to the trans-Golgi network, suggesting Env-mediated effects on tetherin trafficking sequester it from virus assembly sites on the plasma membrane. Finally, we recapitulated these observations in HIV-2-infected CD4 ؉ T-cell lines, demonstrating that tetherin antagonism and sequestration occur at physiological levels of Env expression during virus replication.

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Section: Discussionmentioning

confidence: 96%

Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Tortorec

Neil

2009

J Virol

260

353

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“…Macrophages secrete virions from virus-containing intracellular vacuoles (41). Late endosomes are the principal locations for HIV assembly (42)(43)(44)(45)(46). Importantly, nanoATV retains full antiretroviral activity in late endosomes, as RT activity was substantially decreased in Rab7 and Rab11 vesicles.…”

Section: Discussionmentioning

confidence: 99%

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

Guo

Zhang

Wysocki

et al. 2014

J Virol

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Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ϳ1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nano-ATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance. IMPORTANCEThe need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART concentrations in such sites enhances viral clearance. The current work uncovers a new mechanism by which nanoART can enhance viral clearance over native drug formulations.

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“…34 Consequently, NP are in recycling endosomal compartments where a significant component of the virus' life cycle occurs. 34,38,39 The data suggest that nanoART could enter the cell together with the virus and be located in identical subcellular destinations, further assisting in a targeted delivery to subcellular compartments. This could explain how nanoART are capable of suppressing HIV at low intracellular concentrations.…”

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confidence: 98%

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

Balkundi¹,

Nowacek²,

Veerubhotla³

et al. 2011

IJN

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Nanoformulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz were manufactured by wet milling, homogenization or sonication with a variety of excipients. The chemical, biological, immune, virological, and toxicological properties of these formulations were compared using an established monocyte-derived macrophage scoring indicator system. Measurements of drug uptake, retention, release, and antiretroviral activity demonstrated differences amongst preparation methods. Interestingly, for drug cell targeting and antiretroviral responses the most significant difference among the particles was the drug itself. We posit that the choice of drug and formulation composition may ultimately affect clinical utility.

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The Pericentriolar Recycling Endosome Plays a Key Role in Vpu‐mediated Enhancement of HIV‐1 Particle Release

Cited by 92 publications

References 47 publications

Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

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