Understanding and altering cell tropism of vesicular stomatitis virus

Abstract

Vesicular stomatitis virus (VSV) is a prototypic nonsegmented negative-strand RNA virus. VSV’s broad cell tropism makes it a popular model virus for many basic research applications. In addition, a lack of preexisting human immunity against VSV, inherent oncotropism and other features make VSV a widely used platform for vaccine and oncolytic vectors. However, VSV’s neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe vector. Therefore, it is very important to understand the determinants of VSV tropism and develop strategies to alter it. VSV glycoprotein (G) and matrix (M) protein play major roles in its cell tropism. VSV G protein is responsible for VSV broad cell tropism and is often used for pseudotyping other viruses. VSV M affects cell tropism via evasion of antiviral responses, and M mutants can be used to limit cell tropism to cell types defective in interferon signaling. In addition, other VSV proteins and host proteins may function as determinants of VSV cell tropism. Various approaches have been successfully used to alter VSV tropism to benefit basic research and clinically relevant applications.

Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus

“…We demonstrate that the HPAF-II cell line, the most resistant PDAC cell line, in addition to an upregulated type I IFN signaling and constitutive expression of ISGs, also shows impaired VSV attachment. This result was surprising, as VSV is known for its pantropism and the ability to infect virtually any cell line (of vertebrate or invertebrate origin) in the laboratory (7). Importantly, pretreatment of HPAF-II cells with ruxolitinib did not improve VSV attachment, indicating that type I IFN signaling does not play a …”

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…OVERCOMING RESISTANCE OF SOME CANCERS TO VSV As described above, the oncoselectivity of VSV is largely based on the defective type I IFN-associated antiviral potential of cancer cells compared to normal cells [8,9]. However, in the last few years, it has become clear that some cancers have intact or even upregulated (compared to normal cells) antiviral signalling, which makes them resistant to VSV and other OVs [9,[62][63][64][65].…”

“…Several factors make VSV a promising OV: lack of pre-existing human immunity against VSV, a small and easy to manipulate genome, cytoplasmic replication without risk of host cell transformation, independence of cell cycle and rapid growth to high titres in a broad range of cell lines allowing large-scale production of virus [8,9]. One of the distinctive features of VSV is its pantropism.…”

“…One of the distinctive features of VSV is its pantropism. Ubiquitously expressed cell-surface molecules such as the low-density lipoprotein receptor, phosphatidylserine, sialoglycolipids and heparan sulfate have all been shown to be utilized by VSV for cell attachment [9]. While such pantropism does not allow VSV to distinguish non-malignant ('normal') cells from cancer cells based on their differential receptor expression profiles, the relative independence of VSV from a single receptor can be an advantage, allowing VSV-based OVs to target a wide range of tumour types.…”

“…Oncoselectivity of VSV is generally based on the lower type I IFN-associated antiviral potential of cancer cells compared to normal cells [8,9]. Most tumours have defective or inhibited type I IFN signalling [11], likely because many IFN responses are anti-proliferative, anti-angiogenic and proapoptotic [12].…”