Abstract
The foamy viruses (FV) or spumaviruses are an ancient subfamily of retroviruses that infect a variety of vertebrates. FVs are endemic, but apparently apathogenic, in modern non-human primates. Like other retroviruses, FV replication is inhibited by type-I interferon (IFN). In a previously described screen of IFN-stimulated genes (ISGs), we identified the macaque PHD finger domain protein-11 (PHF11) as an inhibitor of prototype foamy virus (PFV) replication. Here, we show that human and macaque PHF11 inhibit the replication of multiple spumaviruses, but are inactive against several orthoretroviruses. Analysis of other mammalian PHF11 proteins revealed that antiviral activity is host species dependent. Using multiple reporter viruses and cell lines, we determined that PHF11 specifically inhibits a step in the replication cycle that is unique to FVs, namely basal transcription from the FV internal promoter (IP). In so doing, PHF11 prevents expression of the viral transactivator Tas and subsequent activation of the viral LTR promoter. These studies reveal a previously unreported inhibitory mechanism in mammalian cells, that targets a family of ancient viruses and may promote viral latency.
Highlights
Foamy viruses (FVs) or spumaviruses are a subfamily of retroviruses, named for their robust cytopathic effect in tissue culture that is characterized by the formation of large syncytia with small cytoplasmic vacuoles [1]
Foamy viruses have a unique replication strategy and long evolutionary relationship with their vertebrate hosts that has resulted in wide-spread infection of modern species without any apparent pathogenic consequence
We show that PHF11 prevents replication by a previously undescribed mechanism, namely by inhibiting gene expression from an internal viral promoter, a conserved and distinct feature of the foamy viruses
Summary
Foamy viruses (FVs) or spumaviruses are a subfamily of retroviruses, named for their robust cytopathic effect in tissue culture that is characterized by the formation of large syncytia with small cytoplasmic vacuoles [1]. FV infection is endemic in non-human primates and the presence of infectious isolates or endogenous proviruses in many other species suggests that they may be nearly ubiquitous among animals [2, 3] Despite their broad tropism and cytotopathicity in vitro, FVs appear to be apathogenic in vivo, suggesting that they are well controlled by their hosts. FVs regulate their gene expression through the use of two promoters, one within the U3 region of the long terminal repeat (LTR), and an additional internal promoter (IP) that is unique to FVs, within the env gene While both promoters are activated by a viral transactivator protein, Tas (or Bel1) [9], a key feature of this dual reporter configuration is that the internal promoter has modest basal activity in the absence of Tas, and drives initial Tas expression. Latent infection with transcriptionally silent proviruses is frequent, in blood mononuclear cells, during FV infection [10,11,12]
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