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Fang X.-K.,Shanghai JiaoTong University | Fang X.-K.,Shanghai Municipal Veterinary Key laboratory | Wang X.,Shanghai JiaoTong University | Sun T.,Shanghai JiaoTong University | Sun T.,Shanghai Municipal Veterinary Key laboratory
Progress in Biochemistry and Biophysics | Year: 2011

Oncolytic viruses like measles virus, reovirus, adenovirus are promising alternatives in tumor treatment. Vesicular stomatitis virus(VSV) is a potent reagent for tumor virotherapy and has been tried in many types of tumor models. The selectivity of VSV replication in tumor cells has been regarded due to the defective of IFN signaling in tumor cells compared with normal cells. It has been reported that 80% of the tumor cells are type I IFN sinaling defective, which makes oncolytic VSV a promising method for tumor therapy. Recent analysis has demonstrated that defective control of mRNA translation initiation also plays a crucial role in cell permissiveness to VSV. Translation control downstream of PKR activation, frequently dysregulated in many transformed cells, can cooperate with attenuated IFN antiviral activity to facilitated VSV oncolysis. The problem with VSV oncolysis included that cleaning of viruses by host immune system, so the virus can not replicate effectively in tumors, the other is that the viruses can not spread effectively in the tumor tissue because of the tumor microenviroment, but one of the biggest problem is its safety. It was reported that when animals were injected with high dose of wild type VSV, neurotoxicity like hind limb paralysis occurred. There are kinds of strategies to improve safety for oncolytic viruses. Development of tumor antigen targeting VSV is an ideal alternative to improve safety and efficacy of the vector. Adult T cell leukemia (ATL) is a kind of human CD4 T cell tumor caused by HTLV-1, with phenotype of CD4+, CD3+, CD25+ and also CCR5+, CXCR4+. All of the present treatments only arrive partial success, which is underlying the urgency for new therapeutic drugs. Based on these rationales, it was hypothesized that the HIV gp160 pseudotyped VSV (VSV-ΔG-gp160G) could be targeted at ATL cells, because entry of HIV-1 into human CD4 T cell depends on recognition of human CD4 and some co-receptors like CCR5 or CXCR4 and cause fusion between viral and cellular membranes. In the studies, with gp160 cytoplasmic tail replaced with that of VSV G, the HIV-1 envelope protein could be successfully incorporated into VSV. In one step replication curve, VSV-ΔG-gp160G can arrive at the highest titer at around 24 h post infection and the VSV-GFP titer did that at around 12 h post infection, and the titer of VSV-GFP was higher than that of VSV-gp160G, all these indicated that VSV-ΔG-gp160G has been attenuated after pseudotyping. To testify if VSV-ΔG-gp160G could kill ATL tumor cells efficiently, in particular, specifically. HTLV-1 transformed ATL tumor cells and non-ATL cells were infected with VSV-ΔG-gp160G or VSV-GFP for control respectively. The data indicated that the novel VSV could kill CD4 positive ATL cells selectively and potently, but not replicated in CD4 negative non ATL cells. This virus will be promising in treating adult T cell leukemia and lymphoma as well. Source

Sun T.,Shanghai JiaoTong University | Sun T.,Shanghai Municipal Veterinary Key laboratory | Yan X.,Shanghai JiaoTong University | Guo W.,Shanghai JiaoTong University | Zhao D.,Shanghai JiaoTong University
Phytomedicine | Year: 2014

To improve the immune efficacy of protein subunit vaccines, novel adjuvants are needed to elicit a suitable protective immune response and to promote long term immunologic memory. In this work, soyasaponin Ab, a major constituent among group A soyasaponins in soybeans was purified and prepared from soy hypocotyls. The immunomodulatory effects of soyasaponin Ab both in vitro and in vivo were investigated, and its pro-immunomodulatory molecular mechanism was also studied. For in vitro assays, with mouse macrophage cell line RAW264.7 as the studying model, both cytotoxicity and immune stimulatory activity were investigated to evaluate the potential of soyasaponin Ab as the vaccine adjuvant. The results indicated that soyasaponin Ab could be significantly safer than Quillaja saponins (QS). Soyasaponin Ab showed no toxicities over the tested concentration ranges compared to QS. Soyasaponin Ab was proved able to promote releases of inflammatory cytokines like TNFα and IL-1β in a dose-dependent manner. Furthermore, NF-κB signalling was also activated by soyasaponin Ab effectively. In addition, with TLR4 gene expression of RAW264.7 cell inhibited by RNA interference, immune stimulatory effects by soyasaponin Ab dropped down significantly. On the other hand, the in vivo experiment results showed that anti-ovalbumin (OVA) IgG, IgG1, IgG2a, IgG2b were significantly enhanced by the soyasaponin Ab and QS groups (p < 0.05 or p < 0.01). The results suggested that compared to QS, soyasaponin Ab may represent a viable candidate for effective vaccine adjuvant. TLR4 receptor dependent pathway may be involved in immune stimulatory effects of soyasaponin Ab. © 2014 Elsevier GmbH. Source

Fang X.,Shanghai JiaoTong University | Fang X.,Shanghai Municipal Veterinary Key laboratory | Zhang S.,Nanchang University | Sun X.,Shanghai JiaoTong University | And 3 more authors.
Vaccine | Year: 2012

Vesicular stomatitis virus (VSV) is a promising vector for vaccine and oncolysis, but it can also produce acute diseases in cattle, horses, and swine characterized by vesiculation and ulceration of the tongue, oral tissues, feet, and teats. In experimental animals (primates, rats, and mice), VSV has been shown to lead to neurotoxicities, such as hind limb paralysis. The virus matrix protein (M) and glycoprotein (G) are both major pathogenic determinants of wild-type VSV and have been the major targets for the production of attenuated strains. Existing strategies for attenuation included: (1) deletion or M51R substitution in the M protein (VSVΔM51 or VSVM51R, respectively); (2) truncation of the C-terminus of the G protein (GΔ28). Despite these mutations, recombinant VSV with mutated M protein is only moderately attenuated in animals, whereas there are no detailed reports to determine the pathogenicity of recombinant VSV with truncated G protein at high dose. Thus, a novel recombinant VSV (VSVΔM51-GΔ28) as well as other attenuated VSVs (VSVΔM51, VSV-GΔ28) were produced to determine their efficacy as vaccine vectors with low pathogenicity. In vitro studies indicated that truncated G protein (GΔ28) could play a more important role than deletion of M51 (ΔM51) for attenuation of recombinant VSV. VSVΔM51-GΔ28 was determined to be the most attenuated virus with low pathogenicity in mice, with VSV-GΔ28 also showing relatively reduced pathogenicity. Further, neutralizing antibodies stimulated by VSV-GΔ28 proved to be significantly higher than in mice treated with VSVΔM51-GΔ28. In conclusion, among different attenuated VSVs with mutated M and/or G proteins, recombinant VSV with only truncated G protein (VSV-GΔ28) demonstrated ideal balance between pathogenesis and stimulating a protective immune response. These properties make VSV-GΔ28 a promising vaccine vector and vaccine candidate for preventing vesicular stomatitis disease. © 2011 Elsevier Ltd. Source

Fang X.,Shanghai JiaoTong University | Fang X.,Shanghai Municipal Veterinary Key laboratory | Qi B.,Shanghai JiaoTong University | Ma Y.,Shanghai JiaoTong University | And 6 more authors.
Vaccine | Year: 2015

Vesicular stomatitis virus (VSV) causes a serious vesicular disease responsible for economic losses in the livestock industry. Currently, there are no suitable vaccines to prevent VSV infection. Although the structural matrix (M) protein of VSV has been shown to be a virulence factor in rodent models, its role in the pathogenicity of VSV infection in livestock species is unknown. We hypothesized that VSV with mutations in the M protein represents a novel live attenuated vaccine candidate. To test this, we introduced mutations into VSV M protein using reverse genetics and assessed their attenuation both in vitro and in pigs, an important natural host of VSV. A recombinant VSV with a triple amino acid mutation in M protein (VSVMT) demonstrated a significantly reduced ability to inhibit the type I interferon (IFN) signaling pathway and to shutoff host gene expression compared to WT-VSV and a mutant virus with a single amino acid deletion (VSVδM51). Inoculation of pigs with VSVMT induced no apparent vesicular lesions but stimulated virus-neutralizing antibodies and animals were protected against virulent VSV challenge infection. These data demonstrate that the M protein is an important virulence factor for VSV in swine and VSVMT represents a novel vaccine candidate for VSV infections in pigs. © 2015 Elsevier Ltd. Source

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