Cell Membrane–associated Heparan Sulfate Is a Receptor for Prototype Foamy Virus in Human, Monkey, and Rodent Cells

Abstract

Foamy viruses (FVs) (spumaretroviruses) are good alternative to retroviruses as gene therapy vector. Despite four decades since the discovery of FV, its receptor molecule is still unknown. FV vector transduction of human CD34 + cells was inhibited by culture with fibronectin. Because fibronectin contains heparin-binding domain, the interactions of fibronectin with heparan sulfate (HS) on cells might be inhibitory to FV transduction. These observations led us to investigate whether HS is a receptor for FV. Two mutant CHO cell lines (but not parental wild type) lacking cell surface HS but not chondroitin sulfate (CS) were largely resistant to FV attachment and transduction. Inhibition of HS expression using enzymes or chemicals greatly reduced FV transduction in human, monkey, and rodent cells. Raji cells, which lack HS and were largely resistant to FV, were rendered more permissive through ectopic expression of syndecan-1, which contains HS. In contrast, mutant syndecan-1-expressing cells were largely resistant to FV. Our findings indicate that cellular HS is a receptor for FV. Identifying FV receptor will enable better understanding of its entry process and optimal use as gene therapy vector to treat inherited and pathogenic diseases.

Heparan Sulfate Is an Attachment Factor for Foamy Virus Entry

“…While the manuscript was under review, Nasimuzzaman and Persons independently published that heparan sulfate is a receptor molecule for FV entry (28). Their results are in line with our findings with regard to the important role of HS in foamy virus cell entry.…”

Cocirculation of Two env Molecular Variants, of Possible Recombinant Origin, in Gorilla and Chimpanzee Simian Foamy Virus Strains from Central Africa

“…SFV uses heparin sulfate to attach to target cells (47,48), but the receptor for SFV is still unknown (64). Interference studies showed that one cellular receptor is used by all SFVs (44)(45)(46).…”

“…The broad tropism of SFV suggests a ubiquitous cellular receptor (42,43). While all SFVs seem to use the same cellular receptor (44)(45)(46), only heparin sulfate has been identified as an attachment factor so far (47,48).…”

Intravenous injection of a foamy virus vector to correct canine SCID-X1

“…Transactivation of HMGA2 by an enhancer element in a lentiviral vector may have contributed to expansion of myeloid cells in a clinical trial for b-thalassemia major. 41 Despite the broad tropism of the foamy virus receptor, 18 only a single integration in the gut of R2203 (Chr21:20,269,587; 40.3%) appears to result from an off-target transduction. It is very likely, however, that additional offtarget events would be discovered at or near the injection site (eg, vascular endothelium), which represents a general risk to intravenous injection of a replication-deficient virus.…”

“…16,17 Foamy viral vectors have exceptionally broad tissue tropism, attributable to the foamy viral envelope receptor, heparan sulfate, expressed ubiquitously on vertebrate cell surfaces. 18 This allows them to efficiently transduce human HSC The online version of this article contains a data supplement.…”