Scientific Publications by FDA Staff
J Virol 2012 Sep;86(17):9096-104
Detailed mapping of determinants within the porcine endogenous retrovirus envelope surface unit identifies critical residues for human cell infection within the proline-rich region.
Argaw T, Wilson CA
Replication competent porcine endogenous retroviruses (PERV) are either human cell-tropic (PERV-A and PERV-B) or non-human cell tropic (PERV-C). We previously demonstrated that PERV in vitro cell tropism is modulated by 2 residues within the C-terminus of SU and that the PERV receptor binding domain (RBD) extends beyond the VRA and VRB regions, to include the proline rich-region (PRR) of SU (Gemeniano M. et al, 2000, Virology 346: 108-117 ; Argaw. T, et.al 2008, J.Virol. 82, 7483-9). The current study aims to identify the specific elements within the PERV RBD that interact with the C-terminal elements of SU to facilitate human cell infection. We constructed a series of chimeric and mutated envelopes between PERV-A and PERV-C and using pseudotyped retroviral vectors map the human cell tropism-determining sequences within PERV RBD. We show that the PRR from PERV-A is both necessary and sufficient to allow human cell infection when substituted into the homologous region of the PERV-C envelope carrying two C-terminal amino acid substitutions shown to influence human cell tropism, Q374R/I412V (PERV-Crv). Further, substitution of a single amino acid residue in the PRR of the non-human tropic PERV-Crv envelope allows vectors carrying this envelope to infect human cells. Receptor interference assays showed that these modified PERV-C envelopes do not bind either of the human PERV-A receptors, suggesting presence of a distinct human PERV-C receptor. Finally, vectors carrying these modified PERV-C envelopes infect primary human endothelial cells, a cell type likely to be exposed to PERV in clinical use of certain porcine Xenotransplantation products.
|Category: Journal Article|
|PubMed ID: #22696659||DOI: 10.1128/JVI.00738-12|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2012-03-17||Entry Last Modified: 2012-09-28|