Date Published: November 9, 2016
Publisher: Public Library of Science
Author(s): Neil J. Ball, Giuseppe Nicastro, Moumita Dutta, Dominic J. Pollard, David C. Goldstone, Marta Sanz-Ramos, Andres Ramos, Erik Müllers, Kristin Stirnnagel, Nicole Stanke, Dirk Lindemann, Jonathan P. Stoye, William R. Taylor, Peter B. Rosenthal, Ian A. Taylor, Hans-Georg Krausslich.
The Spumaretrovirinae, or foamy viruses (FVs) are complex retroviruses that infect many species of monkey and ape. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. However, there is a paucity of structural information for FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. To probe the functional overlap of FV and orthoretroviral Gag we have determined the structure of a central region of Gag from the Prototype FV (PFV). The structure comprises two all α-helical domains NtDCEN and CtDCEN that although they have no sequence similarity, we show they share the same core fold as the N- (NtDCA) and C-terminal domains (CtDCA) of archetypal orthoretroviral capsid protein (CA). Moreover, structural comparisons with orthoretroviral CA align PFV NtDCEN and CtDCEN with NtDCA and CtDCA respectively. Further in vitro and functional virological assays reveal that residues making inter-domain NtDCEN—CtDCEN interactions are required for PFV capsid assembly and that intact capsid is required for PFV reverse transcription. These data provide the first information that relates the Gag proteins of Spuma and Orthoretrovirinae and suggests a common ancestor for both lineages containing an ancient CA fold.
Spuma- or foamy viruses (FVs) are complex retroviruses that constitute the only members of the Spumaretrovirinae subfamily within the Retroviridae family . They have been isolated from a variety of primate hosts [2–5] as well as from cats [6–8], cattle , horses  and sheep . Endogenous FVs have also been described in sloth , aye-aye  and coelacanth . Prototype foamyvirus (PFV) is a FV isolated from human sources [15, 16]. The PFV genome is highly similar to that of simian foamy virus isolates from chimpanzee (SFVcpz) and so infection in humans is believed to have arisen through zoonotic transmission [17–19]. Nevertheless, even though FVs are endemic within non-human primates and display a broad host range, human-to-human transmission of PFV has never been detected. Moreover, although in cell culture FV infection causes pronounced cytopathic effects , infection in humans and natural hosts is apparently asymptomatic [21–23] making their usage as vectors for gene therapy an attractive proposition .