Insights into Innate Sensing of Prototype Foamy Viruses in Myeloid Cells

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.

Section: Discussionmentioning

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

“…This insensitivity to target intercellular dNTPs is because reverse transcription occurs late in the PFV lifecycle, resulting in a fraction of mature virions harboring nearly complete vDNA [137][138][139][140]. PFV virions with complete vDNA are able establish a productive infection in monocytes; however, incomplete reverse transcriptase products (RTIs) trigger a STING-dependent innate immune response in this cell type [141]. As a result, T and B lymphocytes prominently support viral replication in vivo, a tropism that possibly contributes to the apathogenic phenotype of PFV [142,143].…”

Section: Samhd1 Restriction Of Rna Virusesmentioning

confidence: 99%

SAMHD1 Functions and Human Diseases

Coggins

Mahboubi

Schinazi

et al. 2020

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2′-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi–Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.

“…A few studies supported the existence of an early RT step during foamy virus infection upon entry, which is thought to be relevant at low multiplicities of infection [ 82 , 87 ]. The biological relevance of virions with DNA or RNA genomes is controversially discussed, and the precise proportion of these needs to be determined, especially in vivo [ 14 , 67 , 81 , 82 , 86 , 87 , 88 ].…”

Section: Molecular Biology Of Fvmentioning

confidence: 99%

“…Additionally, a new study suggested that pharmacological inhibitors of the IFN-I response enhance the replication of primary gorilla SFVs [ 125 ]. Very recently, using a myeloid cell model, the innate sensing pathways involved in FV infection were described [ 88 ]. Efficient ISG induction was demonstrated by sensing of full-length PFV genomes but not of minimal vectors in the cytoplasm.…”

Section: Innate Immune Sensing Of Foamy Virusesmentioning

confidence: 99%

“…Efficient ISG induction was demonstrated by sensing of full-length PFV genomes but not of minimal vectors in the cytoplasm. Moreover, this study suggested that viral DNA but not RNA acts as the key stimulator since this innate response was mainly dependent on cellular cGAS and STING, and unaffected by RT inhibition during entry [ 88 ]. Foamy viral escape from sensing may be mediated in PFV infections by Gag-induced endosomal autophagy that facilitates the clearance of stress granules to repress an IFN-I response of the infected cell [ 126 ].…”

Section: Innate Immune Sensing Of Foamy Virusesmentioning

confidence: 99%

See 1 more Smart Citation

Foamy Viruses, Bet, and APOBEC3 Restriction

Vasudevan

Becker

Luedde

et al. 2021

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.