RGD Reference Report - Tetherin Inhibits Cell-Free Virus Dissemination and Retards Murine Leukemia Virus Pathogenesis. - Rat Genome Database

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Tetherin Inhibits Cell-Free Virus Dissemination and Retards Murine Leukemia Virus Pathogenesis.

Authors: Liberatore, Rachel A  Mastrocola, Emily J  Powell, Chelsea  Bieniasz, Paul D 
Citation: Liberatore RA, etal., J Virol. 2017 May 26;91(12). pii: JVI.02286-16. doi: 10.1128/JVI.02286-16. Print 2017 Jun 15.
RGD ID: 14398820
Pubmed: PMID:28381565   (View Abstract at PubMed)
PMCID: PMC5446635   (View Article at PubMed Central)
DOI: DOI:10.1128/JVI.02286-16   (Journal Full-text)

The relative contributions of cell-free virion circulation and direct cell-to-cell transmission to retroviral dissemination and pathogenesis are unknown. Tetherin/Bst2 is an antiviral protein that blocks enveloped virion release into the extracellular milieu but may not inhibit cell-to-cell virus transmission. We developed live-cell imaging assays which show that tetherin does not affect Moloney murine leukemia virus (MoMLV) spread, and only minimally affects vesicular stomatitis virus (VSV) spread, to adjacent cells in a monolayer. Conversely, cell-free MLV and VSV virion yields and VSV spread to distal cells were dramatically reduced by tetherin. To elucidate the roles of tetherin and cell-free virions during in vivo viral dissemination and pathogenesis, we developed mice carrying an inducible human tetherin (hTetherin) transgene. While ubiquitous hTetherin expression was detrimental to the growth and survival of mice, restriction of hTetherin expression to hematopoietic cells gave apparently healthy mice. The expression of hTetherin in hematopoietic cells had little or no effect on the number of MoMLV-infected splenocytes and thymocytes. However, hTetherin expression significantly reduced cell-free plasma viremia and also delayed MoMLV-induced disease. Overall, these results suggest that MoMLV spread within hematopoietic tissues and cell monolayers involves cell-to-cell transmission that is resistant to tetherin but that virion dissemination via plasma is inhibited by tetherin and is required for full MoMLV pathogenesis.IMPORTANCE Retroviruses are thought to spread primarily via direct cell-to-cell transmission, yet many have evolved to counteract an antiviral protein called tetherin, which may selectively inhibit cell-free virus release. We generated a mouse model with an inducible tetherin transgene in order to study how tetherin affects retroviral dissemination and on which cell types its expression is required to do so. We first developed a novel in vitro live-cell imaging assay to demonstrate that while tetherin does indeed dramatically reduce cell-free virus spreading, it has little to no effect on direct cell-to-cell transmission of either vesicular stomatitis virus (VSV) or the retrovirus MoMLV. Using our transgenic mouse model, we found that tetherin expression on hematopoietic cells resulted in the specific reduction of MoMLV cell-free plasma viremia but not the number of infected hematopoietic cells. The delay in disease associated with this scenario suggests a role for cell-free virus in retroviral disease progression.



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RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BST2HumanRetroviridae Infections disease_progressionIDA  RGD 
Bst2RatRetroviridae Infections disease_progressionISOBST2 (Homo sapiens) RGD 
Bst2MouseRetroviridae Infections disease_progressionISOBST2 (Homo sapiens) RGD 
BST2HumanViremia  IDA associated with Retroviridae Infections;RGD 
Bst2RatViremia  ISOBST2 (Homo sapiens)associated with Retroviridae Infections;RGD 
Bst2MouseViremia  ISOBST2 (Homo sapiens)associated with Retroviridae Infections;RGD 

Objects Annotated

Genes (Rattus norvegicus)
Bst2  (bone marrow stromal cell antigen 2)

Genes (Mus musculus)
Bst2  (bone marrow stromal cell antigen 2)

Genes (Homo sapiens)
BST2  (bone marrow stromal cell antigen 2)


Additional Information