The infectivity and host range of the ecotropic porcine endogenous retrovirus, PERV-C, is modulated by residues in the C-terminal region of its surface envelope protein

Abstract

Endogenous retroviral genetic material serves as a reservoir for the generation of retroviral pathogens by recombination between activated endogenous or exogenous infectious agents. Some porcine tissues actively express infectious porcine endogenous retroviruses (PERVs). Of the three classes of PERV characterized to date, two, PERV-A and B, are capable of infecting human cells in vitro, whereas PERV-C cannot. Here, we demonstrate that the PERV-C envelope surface protein (SU) when disassociated from its C-terminus binds human cells. Further, we show that PERV-C binding to human cells is not inhibited in 293 cells productively infected with PERV-A, confirming that the molecule PERV-C interacts with on human cells is distinct from that used by PERV-A. Moreover, we demonstrate that the envelope region encompassing the proline-rich region is required for binding to cells in addition to the putative variable region A (VRA) and B (VRB). The region in the C-terminus of the SU that alters the binding and infectivity properties of PERV-C differs by only nine residues from the analogous region of PERV-A. Caution may be warranted even when a xenotransplantation product is from source pigs that do not express human-tropic viruses, as minimal mutations within PERV-C combined with selection in a human recipient could render PERV-C infectious in humans.

Cell Surface Expression of the Bovine Leukemia Virus-Binding Receptor on B and T Lymphocytes Is Induced by Receptor Engagement

“…Notably, we find that binding to the BLV receptor did not require the presence of immediately downstream PRR sequences of BLV Env. This is of particular importance since, in the context of HTLV, retroviral PRR or downstream sequences may bind to cell surface components other than the primary receptor (45,46), and sequences outside the RBD in some gammaretrovirus SU appear to modulate or block binding and infection (47)(48)(49). Nevertheless, in the context of the BLV envelope, an Env-specific binding interference assay demonstrated that the BLV RBD alone decreased B RBD binding to levels similar to that detected in the presence of the entire BLV Env.…”

Methods and Tools for Detection and Evaluation of the Risks of Porcine Endogenous Retrovirus in Porcine to Human Xenotransplantation

“…We have also shown that PERV-C RBD can bind human cells specifically, in a dosedependent manner (Gemeniano, Mpanju et al 2006). More recently, we demonstrated that relatively few amino acid changes in the PERV-C envelope can allow infection of human cells (Argaw, Figueroa et al 2008).…”

“…Harrison et al used a naturally occurring recombinant of PERV-A and PERV-C with high titer on human cells compared to parental PERV-A and showed two regions that correlated with increased infection on human cells: amino acid residue 140 that lies between VRA and VRB and additional sequences within the PRR (Harrison, Takeuchi et al 2004). Our laboratory has also shown that sequences within the C-terminal region of the SU influence human cell infectivity (Gemeniano, Mpanju et al 2006;Argaw, Figueroa et al 2008).…”

“…Using a fusion protein based on the rabbit immunoglobulin heavy chain, we showed several years ago that PERV envelope binding requires a region beyond the prototypical receptor binding domain (RBD) for gammaretroviruses. As shown in Figure 2, the RBD that we mapped using this approach encompassed not just the variable regions A and B (VRA and VRB) as has been shown for other related viruses, but also requires the proline-rich region (PRR) (Gemeniano, Mpanju et al 2006). Using the pseudotype assay described in section 2.1.5, we and others have tried to identify more precisely the regions of the envelope required for human cell infection.…”

Development of sensitive methods for detection of porcine endogenous retrovirus-C (PERV-C) in the genome of pigs

“…In addition, there are also other reasons not to use PERV-C positive animals. First, the ability of PERV-C to infect cells that do not harbor the specific receptor by receptor-independent infection (Lavillette and Kabat, 2004), and second, mutations in the envelope protein of PERV-C may change the tropism towards human cells (Gemeniano et al, 2006). These data indicate, that breeding out PERV-C will reduce the risk of PERV transmission in xenotransplantation.…”