Comparison of infectivity and spread between HSV-1 and HSV-2 based oncolytic viruses on tumor cells with different receptor expression profiles.

Xinping Fu,Xiaoliu Zhang,Pin-Yi Wang,Timothy P Cripe,Lihua Tao

doi:10.18632/oncotarget.25096

Abstract

Herpes simplex virus (HSV) is one of the many viruses that have been modified or adapted for oncolytic purposes. There are two serotypes of HSV, HSV-1 and HSV-2. The majority of oncolytic HSVs, including T-VEC which has recently been approved by the US Food and Drug Administration (FDA) for clinical use in treating late stage melanoma patients, are derived from HSV-1. Recently, we and others have developed several HSV-2 based oncolytic viruses. During our in vitro characterization of oncolytic viruses developed from both serotypes (Baco-1 from HSV-1 and FusOn-H2 from HSV-2), we noticed there is a subpopulation of cancer cells in which both viruses could infect but only FusOn-H2 could spread from cell to cell on monolayers. This observation prompted us to investigate the virus receptor expression profiles in these and other tumor cells. Our data show the following: 1) This subpopulation of tumor cells only express nectin-2, not the other two major receptors (HVEM or nectin-1). 2) Baco-1 grows to a higher titer than FusOn-H2 in this subpopulation of tumor cells, but the latter kills these tumor cells more efficiently than the former. 3) FusOn-H2 is effective at treating tumors formed from these tumor cells while Baco-1 is completely ineffective. Our results suggest that this subpopulation of tumor cells may be intrinsically resistant to the therapeutic effect of a HSV-1 based oncolytic virus but they remain sensitive to a HSV-2 based virotherapy.

Highlights

Herpes simplex virus (HSV) is one of the many human and animal viruses that have been modified or adapted for oncolytic purpose
Our results suggest that this subpopulation of tumor cells may be intrinsically resistant to the therapeutic effect of a HSV-1 based oncolytic virus but they remain sensitive to a HSV-2 based virotherapy
Our data suggest the existence of a subpopulation of tumor cells that only express the nectin-2 but not the other receptors, and that only the HSV-2 (FusOn-H2) but not HSV-1 (Baco-1) based oncolytic virus can spread cell to cell in these tumor cells

Summary

Introduction

Herpes simplex virus (HSV) is one of the many human and animal viruses that have been modified or adapted for oncolytic purpose. Lytic infection by HSV usually kills target cells much more rapidly than infection by other DNA viruses. Rapid replication and spreading among target cells appear to be vital properties allowing a virus to execute its full oncolytic potential in vivo, as the body’s immune mechanism may be more likely to restrict the spread of slower growing viruses. HSV has a wide tropism and oncolytic viruses derived from it can be applied therapeutically to many different types of tumors. In principle, this property should protect against the rapid development of resistance to virotherapy using HSV in contrast to other oncolytic viruses such as those derived from adenoviruses.

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