Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses

ABSTRACT Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impa...

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Autores principales:	Ryan P. McNamara, Lindsey M. Costantini, T. Alix Myers, Blake Schouest, Nicholas J. Maness, Jack D. Griffith, Blossom A. Damania, Andrew G. MacLean, Dirk P. Dittmer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	HIV Nef SIV exosomes extracellular vesicles microvesicles Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c19a962726cf4ca995b73d4cea8db3e4
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spelling	oai:doaj.org-article:c19a962726cf4ca995b73d4cea8db3e42021-11-15T15:53:26ZNef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses10.1128/mBio.02344-172150-7511https://doaj.org/article/c19a962726cf4ca995b73d4cea8db3e42018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02344-17https://doaj.org/toc/2150-7511ABSTRACT Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef-positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells. IMPORTANCE Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non-infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo. Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression.Ryan P. McNamaraLindsey M. CostantiniT. Alix MyersBlake SchouestNicholas J. ManessJack D. GriffithBlossom A. DamaniaAndrew G. MacLeanDirk P. DittmerAmerican Society for MicrobiologyarticleHIVNefSIVexosomesextracellular vesiclesmicrovesiclesMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV Nef SIV exosomes extracellular vesicles microvesicles Microbiology QR1-502
spellingShingle	HIV Nef SIV exosomes extracellular vesicles microvesicles Microbiology QR1-502 Ryan P. McNamara Lindsey M. Costantini T. Alix Myers Blake Schouest Nicholas J. Maness Jack D. Griffith Blossom A. Damania Andrew G. MacLean Dirk P. Dittmer Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
description	ABSTRACT Extracellular vesicles (EVs) or exosomes have been implicated in the pathophysiology of infections and cancer. The negative regulatory factor (Nef) encoded by simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) plays a critical role in the progression to AIDS and impairs endosomal trafficking. Whether HIV-1 Nef can be loaded into EVs has been the subject of controversy, and nothing is known about the connection between SIV Nef and EVs. We find that both SIV and HIV-1 Nef proteins are present in affinity-purified EVs derived from cultured cells, as well as in EVs from SIV-infected macaques. Nef-positive EVs were functional, i.e., capable of membrane fusion and depositing their content into recipient cells. The EVs were able to transfer Nef into recipient cells. This suggests that Nef readily enters the exosome biogenesis pathway, whereas HIV virions are assembled at the plasma membrane. It suggests a novel mechanism by which lentiviruses can influence uninfected and uninfectable, i.e., CD4-negative, cells. IMPORTANCE Extracellular vesicles (EVs) transfer biologically active materials from one cell to another, either within the adjacent microenvironment or further removed. EVs also package viral RNAs, microRNAs, and proteins, which contributes to the pathophysiology of infection. In this report, we show that both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) incorporate the virus-encoded Nef protein into EVs, including EVs circulating in the blood of SIV-infected macaques and that this presents a novel mechanism of Nef transfer to naive and even otherwise non-infectable cells. Nef is dispensable for viral replication but essential for AIDS progression in vivo. Demonstrating that Nef incorporation into EVs is conserved across species implicates EVs as novel mediators of the pathophysiology of HIV. It could help explain the biological effects that HIV has on CD4-negative cells and EVs could become biomarkers of disease progression.
format	article
author	Ryan P. McNamara Lindsey M. Costantini T. Alix Myers Blake Schouest Nicholas J. Maness Jack D. Griffith Blossom A. Damania Andrew G. MacLean Dirk P. Dittmer
author_facet	Ryan P. McNamara Lindsey M. Costantini T. Alix Myers Blake Schouest Nicholas J. Maness Jack D. Griffith Blossom A. Damania Andrew G. MacLean Dirk P. Dittmer
author_sort	Ryan P. McNamara
title	Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
title_short	Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
title_full	Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
title_fullStr	Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
title_full_unstemmed	Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses
title_sort	nef secretion into extracellular vesicles or exosomes is conserved across human and simian immunodeficiency viruses
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c19a962726cf4ca995b73d4cea8db3e4
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Nef Secretion into Extracellular Vesicles or Exosomes Is Conserved across Human and Simian Immunodeficiency Viruses

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