Efficient infection of mature skeletal muscle with herpes simplex virus vectors by using dextran sulfate as a co-receptor

Abstract

The use of herpes simplex virus (HSV) vectors for gene chondroitin ABC lyase, HSV infection was restored, which delivery to skeletal muscle is hampered by a maturationsuggests that virus secondary receptors were present but dependent loss of muscle fiber infectivity. Previous studies not readily accessible to the virus in the intact myofiber. of HSV type 1 (HSV-1) infection in the rodent show that Surprisingly, we also found that HSV-1 infectivity could be the loss of infectivity may be due, at least in part, to the restored in vitro and in vivo by exposing myofibers to low development of the basal lamina throughout the course of concentrations of the glycosaminoglycan analog dextran maturation, which may block the initial events in HSV infecsulfate, which appears to act as a surrogate receptor to tion. To initiate infection, HSV normally attaches to cell surstabilize the virus at the myofiber surface such that HSV face heparan sulfate, which stabilizes the virus such that can engage additional receptors. This demonstration that it can interact with secondary protein receptors required the basal lamina is not an absolute block to HSV-1 infecfor entry into host cells. In this study, we demonstrate that tion is remarkable because it allows for the nondestructive heparan sulfate biosynthesis is downregulated during skeltargeting of HSV-1 to mature myofibers and greatly etal muscle maturation. When myofibers were treated with expands the usefulness of HSV as a gene therapy vector a variety of enzymes, including collagenase type IV or for the treatment of inherited and acquired diseases.

Polymers for Improving the In Vivo Transduction Efficiency of AAV2 Vectors

“…It has been reported that the synthesis of heparan sulfate proteoglycan is down-regulated during murine skeletal muscle maturation, and this has been proposed to be responsible for the loss of HSV infectivity [29] (heparan sulfate acts as a co-receptor for attachment of HSV to cells). Based on this report, we propose the hypothesis that due to low levels of heparan sulfate proteoglycan in muscle, cationic polymers improve the transduction by facilitating the primary interaction between virus and the muscle fibers.…”

Efficiency of Protein Transduction Is Cell Type-dependent and Is Enhanced by Dextran Sulfate

“…The use of DS preincubation presents a technique to potently enhance PTD delivery of biologically relevant cargoes to poorly transducible, GAG-low cell lines and primary cells for their manipulation in vitro and ex vivo. Since primary tissues, such as hematopoietic stem cells and differentiated muscle tissue, are known to have down-regulated GAG surface expression, DS might be used to enhance ex vivo protein transduction of these cell types (63,64). Furthermore, the widespread presence of short, arginine/lysine-rich stretches of residues within proteins opens up the possibility that, with or without DS treatment, such proteins may be capable of receptorless entry into cells without the need for modification of their primary sequences.…”

Utilization of Sialic Acid as a Coreceptor Enhances Reovirus Attachment by Multistep Adhesion Strengthening

“…Alternatively, the virus binding site on the 1 head receptor may be proximal to the cell surface or otherwise sterically inaccessible to soluble virus. In this scenario, virus binding to sialic acid may serve to insert the 1 head into the glycocalyx to permit interaction between this receptor and 1 (63,64). Finally, 1-sialic acid interactions may induce a conformational change in 1 that places the head RBD in a state that displays higher affinity for its receptor, in a mechanism analogous to CD4-induced conformational changes that expose chemokine receptor-binding residues on HIV gp120 (4 -6), although a 1 conformational change alone is not sufficient to enhance attachment, since incubation with SLL inhibits rather than enhances SAϩ binding.…”