Shared and cell type-specific adaptation strategies of Gag and Env yield high titer bovine foamy virus variants

Bao, Qiuying; Hotz‐Wagenblatt, Agnes; Betts, Matthew J.; Hipp, Michaela; Hugo, Annette; Pougialis, Georgios; Lei-Rossmann, Janet; Löchelt, Martin

doi:10.1016/j.meegid.2020.104287

Cited by 7 publications

(20 citation statements)

References 13 publications

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“…BFV as a well-established infection model in life-stock animals (cattle and sheep) [13,14] BFV as the only known FV in the general human food chain (beef and dairy products) [15,16] BFV Riems as the only FV passaged exclusively on primary and homologous host cells [17,18] Integrase domain: disrupted HH-CC zinc finger and unique sequence insertion into the extreme C-terminus [19] Detailed understanding of gene expression and transactivation of a non-simian FV [20,21] RNA Pol III miRNAs, unique precursor structure and their functions [14,22,23] Extremely tight cell association and identification of residues critical for this phenotype [24][25][26] Detailed understanding of new restriction factors against FVs [27] Broad tissue tropism and gene expression in BFV-infected calves [5,28] Although a so-called prototype (and/or primate) FV exists in the literature, conserved, prototypic features, besides those basic characteristics that led to the establishment of an independent subfamily of FVs, are currently only partially known. Here, an unbiased comparison of distant FVs and their replication strategies might be worth trying to discriminate basic from deduced, secondary features.…”

Section: Subject/topic Referencesmentioning

confidence: 99%

“…At the same site in Gag in some high titer (HT) cell-free BFV-Riems variants, insertions, and duplications occurred. However, their impact on BFV titers has not been studied [26]. The Gag-Env interaction is very important for the budding and release of FV virions.…”

Section: Function and Localization Of Gagmentioning

confidence: 99%

“…The resultant HT variants had independently gained the capacity to spread via cell-free particles, but still also use cell-cell transmission [24]. Genetic studies indicate that consistent and cell type-specific, as well as cell-type-independent adaptive changes, occurred in Gag and Env as well as in the LTR regions where larger changes had also been observed [26] (Bao, Stricker, Hotz-Wagenblatt, and Löchelt, to be published). Importantly, cell-free HT BFV-Riems is still neutralized by serum from naturally infected cows [24].…”

Section: Highly Cell-associated Spread At Least In Cell Cultures-whamentioning

confidence: 99%

“…Some of these vectors have been tested beyond cell cultures in small lab animals (mostly mice), but also in outbred hosts like dog (ex vivo PFV-based gene transfer vectors to treat canine leukocyte adhesion deficiency [162]) and cats (FFV-based replication-competent vaccine vectors [163,164]). The recent cloning of full-length BFV genomes that allows for cell-free transmission [14,25,26] is an important prerequisite for conducting and extending corresponding studies also for BFV.…”

Section: Utilization Of Bfv As Viral Vector For Translational Applicamentioning

confidence: 99%

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Bovine Foamy Virus: Shared and Unique Molecular Features In Vitro and In Vivo

Materniak-Kornas

Tan

Heit-Mondrzyk

et al. 2019

Viruses

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The retroviral subfamily of Spumaretrovirinae consists of five genera of foamy (spuma) viruses (FVs) that are endemic in some mammalian hosts. Closely related species may be susceptible to the same or highly related FVs. FVs are not known to induce overt disease and thus do not pose medical problems to humans and livestock or companion animals. A robust lab animal model is not available or is a lab animal a natural host of a FV. Due to this, research is limited and often focused on the simian FVs with their well-established zoonotic potential. The authors of this review and their groups have conducted several studies on bovine FV (BFV) in the past with the intention of (i) exploring the risk of zoonotic infection via beef and raw cattle products, (ii) studying a co-factorial role of BFV in different cattle diseases with unclear etiology, (iii) exploring unique features of FV molecular biology and replication strategies in non-simian FVs, and (iv) conducting animal studies and functional virology in BFV-infected calves as a model for corresponding studies in primates or small lab animals. These studies gained new insights into FV-host interactions, mechanisms of gene expression, and transcriptional regulation, including miRNA biology, host-directed restriction of FV replication, spread and distribution in the infected animal, and at the population level. The current review attempts to summarize these findings in BFV and tries to connect them to findings from other FVs.

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Section: Subject/topic Referencesmentioning

confidence: 99%

Section: Function and Localization Of Gagmentioning

confidence: 99%

Section: Highly Cell-associated Spread At Least In Cell Cultures-whamentioning

confidence: 99%

Section: Utilization Of Bfv As Viral Vector For Translational Applicamentioning

confidence: 99%

See 2 more Smart Citations

Bovine Foamy Virus: Shared and Unique Molecular Features In Vitro and In Vivo

Materniak-Kornas

Tan

Heit-Mondrzyk

et al. 2019

Viruses

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“…To conduct reverse genetic experiments, cloned BFV genomes selected for high titer cell-free transmission in bovine MDBK cells [28,30] were further optimized by replacing the U3 region of the 5 LTR by the strong and constitutively active CMV immediate early (IE) promoter using standard cloning strategies as described previously for feline FV [31]. BFV genomes lacking the complete BFV miRNA cassette were obtained by fusion PCR mutagenesis as described [32,33], utilizing the following primer pair 1 (fw-NheI-ENV; 5 -GTTAGTCATCGGAAT-ATTGAGATGGCTAGCGGTG-GGACGCCGG-3 and rev-AscI-U3; 5 -CAGATCTCAGGCGCGCCGGTTCCTTATTGAGATGTC-TTCG-3 ) and primer pair 2 (fw-AscI-AclI-U3, 5 -AATAAGGAACCGGCGCGCCTGAGATCTGTGTGTGACTACATTGAACGTT-GATGTATAACTAGAAGAATAAGATTAAG-3 and rev-ApaI-U5; 5 -GACTCACTATAGGGCGAATTG-GGCCCTTGTTGTGACCTTCTCC-3 ; all from Sigma).…”

Section: Molecular Cloningmentioning

confidence: 99%

Functional Analyses of Bovine Foamy Virus-Encoded miRNAs Reveal the Importance of a Defined miRNA for Virus Replication and Host–Virus Interaction

Cao

Stricker

Hotz‐Wagenblatt

et al. 2020

Viruses

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In addition to regulatory or accessory proteins, some complex retroviruses gain a repertoire of micro-RNAs (miRNAs) to regulate and control virus–host interactions for efficient replication and spread. In particular, bovine and simian foamy viruses (BFV and SFV) have recently been shown to express a diverse set of RNA polymerase III-directed miRNAs, some with a unique primary miRNA double-hairpin, dumbbell-shaped structure not known in other viruses or organisms. While the mechanisms of expression and structural requirements have been studied, the functional importance of these miRNAs is still far from understood. Here, we describe the in silico identification of BFV miRNA targets and the subsequent experimental validation of bovine Ankyrin Repeat Domain 17 (ANKRD17) and Bax-interacting factor 1 (Bif1) target genes in vitro and, finally, the suppression of ANKRD17 downstream genes in the affected pathway. Deletion of the entire miRNA cassette in the non-coding part of the U3 region of the long terminal repeats attenuated replication of corresponding BFV mutants in bovine cells. This repression can be almost completely trans-complemented by the most abundant miRNA BF2-5p having the best scores for predicted and validated BFV miRNA target genes. Deletion of the miRNA cassette does not grossly affect particle release and overall particle composition.

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Plasma antibodies from humans infected with zoonotic simian foamy virus do not inhibit cell-to-cell transmission of the virus despite binding to the surface of infected cells

et al. 2022

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Zoonotic simian foamy viruses (SFV) establish lifelong infection in their human hosts. Despite repeated transmission of SFV from nonhuman primates to humans, neither transmission between human hosts nor severe clinical manifestations have been reported. We aim to study the immune responses elicited by chronic infection with this retrovirus and previously reported that SFV-infected individuals generate potent neutralizing antibodies that block cell infection by viral particles. Here, we assessed whether human plasma antibodies block SFV cell-to-cell transmission and present the first description of cell-to-cell spreading of zoonotic gorilla SFV. We set-up a microtitration assay to quantify the ability of plasma samples from 20 Central African individuals infected with gorilla SFV and 9 uninfected controls to block cell-associated transmission of zoonotic gorilla SFV strains. We used flow-based cell cytometry and fluorescence microscopy to study envelope protein (Env) localization and the capacity of plasma antibodies to bind to infected cells. We visualized the cell-to-cell spread of SFV by real-time live imaging of a GFP-expressing prototype foamy virus (CI-PFV) strain. None of the samples neutralized cell-associated SFV infection, despite the inhibition of cell-free virus. We detected gorilla SFV Env in the perinuclear region, cytoplasmic vesicles and at the cell surface. We found that plasma antibodies bind to Env located at the surface of cells infected with primary gorilla SFV strains. Extracellular labeling of SFV proteins by human plasma samples showed patchy staining at the base of the cell and dense continuous staining at the cell apex, as well as staining in the intercellular connections that formed when previously connected cells separated from each other. In conclusion, SFV-specific antibodies from infected humans do not block cell-to-cell transmission, at least in vitro, despite their capacity to bind to the surface of infected cells. Trial registration: Clinical trial registration: www.clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT03225794/.

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Shared and cell type-specific adaptation strategies of Gag and Env yield high titer bovine foamy virus variants

Cited by 7 publications

References 13 publications

Bovine Foamy Virus: Shared and Unique Molecular Features In Vitro and In Vivo

Bovine Foamy Virus: Shared and Unique Molecular Features In Vitro and In Vivo

Functional Analyses of Bovine Foamy Virus-Encoded miRNAs Reveal the Importance of a Defined miRNA for Virus Replication and Host–Virus Interaction

Plasma antibodies from humans infected with zoonotic simian foamy virus do not inhibit cell-to-cell transmission of the virus despite binding to the surface of infected cells

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