Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan

Abstract

Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope-receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced.

Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells

“…S1 shows high levels of HS revealed by the mAb 10E4 in the human intestinal epithelial cell line HT-29 and a marked reduction in cell staining after heparinase II treatment. Cleavage of HS by heparinase III (heparitinase) results not only in the destruction of the epitope recognized by the anti-HS mAb 10E4 but also in the expression of a neoepitope recognized by the mAb 3G10 ( Jones et al, 2005 ; Kureishy et al, 2006 ). Consistent with these studies, we found that treatment of spermatozoa with heparinase III resulted in a diminished expression of the HS epitope 10E4 (69 ± 13% decrease in the MFI; mean ± SEM; n = 4; P < 0.05) and the neoexpression of the epitope 3G10 ( Fig.…”

Symmetry-Related Clustering of Positive Charges Is a Common Mechanism for Heparan Sulfate Binding in Enteroviruses

“…Several viruses are known to interact with HSPG molecules at the cell surface as a prelude to infection, and the list of such viruses continues to grow (8,31,50). These include some serotypes of adenovirus which can show differential preference over the various conformations of HSPG that can occur (46).…”