Antitumor effect of the LIVP-GFP recombinant vaccinia virus

Petrov, Igor; Гончарова, Е. П.; Колосова, И. В.; Pozdnyakov, S. G.; Щелкунов, С. Н.; Zenkova, Marina A.; Власов, В. В.

doi:10.1134/s0012496613040133

Cited by 12 publications

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“…The recombinant VACV strain LIVP-GFP containing the gfp gene inserted in the thymidine kinase locus of the virus was constructed at the State Research Center of Virology and Biotechnology “VECTOR” [ 28 ]. The insertion of gfp was verified by sequence analysis as well as GFP production in the CV-1 African green monkey cell line infected with the virus.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, we compared the antitumour efficacy of LIVP-GFP in RLS-40 lymphosarcoma cells with melanoma B-16 in immunocompetent mice, taking into consideration the differential ability of LIVP-GFP to replicate and kill cells in this tumour cell line. We had previously determined that intratumoural administration of the LIVP-GFP virus resulted in a significant inhibition of tumour growth in mice bearing melanoma B-16 [ 28 ]. Inhibition of the growth of such a quick-growing tumours as melanoma B16 after a single administration of the LIVP–GFP virus indicates its high antitumour potential.…”

Section: Discussionmentioning

confidence: 99%

“…Vaccinia virus LIVP-GFP was modified by deletion of the thymidine kinase gene and by insertion of the DNA sequence encoding the green fluorescent protein (GFP) protein. The construction of mutant vaccinia virus LIVP-GFP was described recently [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

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Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro

et al. 2016

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BackgroundTumour resistance to a wide range of drugs (multiple drug resistant, MDR) acquired after intensive chemotherapy is considered to be the main obstacle of the curative treatment of cancer patients. Recent work has shown that oncolytic viruses demonstrated prominent potential for effective treatment of diverse cancers. Here, we evaluated whether genetically modified vaccinia virus (LIVP-GFP) may be effective in treatment of cancers displaying MDR phenotype.MethodsLIVP-GFP replication, transgene expression and cytopathic effects were analysed in human cervical carcinomas KB-3-1 (MDR−), KB-8-5 (MDR+) and in murine melanoma B-16 (MDR−), murine lymphosarcomas RLS and RLS-40 (MDR+). To investigate the efficacy of this therapy in vivo, we treated immunocompetent mice bearing murine lymphosarcoma RLS-40 (MDR+) (6- to 8-week-old female CBA mice; n = 10/group) or melanoma B-16 (MDR−) (6- to 8-week-old female C57Bl mice; n = 6/group) with LIVP-GFP (5 × 107 PFU of virus in 0.1 mL of IMDM immediately and 4 days after tumour implantation).ResultsWe demonstrated that LIVP-GFP replication was effective in human cervical carcinomas KB-3-1 (MDR−) and KB-8-5 (MDR+) and in murine melanoma B-16 (MDR−), whereas active viral production was not detected in murine lymphosarcomas RLS and RLS-40 (MDR+). Additionally, it was found that in tumour models in immunocompetent mice under the optimized regimen intratumoural injections of LIVP-GFP significantly inhibited melanoma B16 (33 % of mice were with complete response after 90 days) and RLS-40 tumour growth (fourfold increase in tumour doubling time) as well as metastasis.ConclusionThe anti-tumour activity of LIVP-GFP is a result of direct oncolysis of tumour cells in case of melanoma B-16 because the virus effectively replicates and destroys these cells, and virus-mediated activation of the host immune system followed by immunologically mediated destruction of of tumour cells in case of lymphosarcoma RLS-40. Thus, the recombinant vaccinia virus LIVP-GFP is able to inhibit the growth of malignant cells with the MDR phenotype and tumour metastasis when administered in the early stages of tumour development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1002-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro

et al. 2016

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“…Вирусы, культура клеток. В работе использовали клон 14 штамма VACV LIVP (LIVP), полученный нами ра нее трехкратным пересевом через бляшку изпод агарозного покрытия методом предельного разведения (Yaku bitskiy et al, 2015), а также штамм LIVPGFP, получен ный на его основе встройкой гена зеленого флуоресцент ного бел ка в состав вирусного гена тимидинкиназы (Petrov et al, 2013…”

Section: материалы и методыunclassified

Mutations in the <i>A34R</i> gene increase the immunogenicity of vaccinia virus

et al. 2021

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Vaccination is the most simple and reliable approach of protection to virus infections. The most effective agents are live vaccines, usually low-virulence organisms for humans and closely related to pathogenic viruses or attenuated as a result of mutations/deletions in the genome of pathogenic virus. Smallpox vaccination with live vaccinia virus (VACV) closely related to smallpox virus played a key role in the success of the global smallpox eradication program carried out under the World Health Organization auspices. As a result of the WHO decision as of 1980 to stop smallpox vaccination, humankind has lost immunity not only to smallpox, but also to other zoonotic, orthopoxviruscaused human infections. This new situation allows orthopoxviruses to circulate in the human population and, as a consequence, to alter several established concepts of the ecology and range of sensitive hosts for various orthopoxvirus species. Classic VACV-based live vaccine for vaccination against orthopoxvirus infections is out of the question, because it can cause severe side effects. Therefore, the development of new safe vaccines against orthopoxviral infections of humans and animals is an important problem. VACV attenuation by modern approaches carried out by targeted inactivation of certain virus genes and usually leads to a decrease in the effectiveness of VACV in vivo propagation. As a result, it can cause a diminishing of the immune response after administration of attenuated virus to patients at standard doses. The gene for thymidine kinase is frequently used for insertion/inactivation of foreign genes and it causes virus attenuation. In this research, the effect of the introduction of two point mutations into the A34R gene of attenuated strain LIVP-GFP (ТК–), which increase the yield of extracellular enveloped virions (EEV), on the pathogenicity and immunogenicity of VACV LIVP-GFP-A34R administered intranasally to laboratory mice were studied. It was shown that increase in EEV production by recombinant strain VACV LIVP-GFP-A34R does not change the attenuated phenotype characteristic of the parental strain LIVP-GFP, but causes a significantly larger production of VACV-specific antibodies.

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“…It is known that VACV vaccine strains are genetically heterogenic. Therefore, previously, for genetic engineering reconstruction experiments, we obtained the clonal variant 14 of the LIVP strain (LIVP-14) [10], which was the parental strain in designing the fourth-generation live attenuated smallpox vaccine [11] and the oncolytic VACV variant [12][13][14]. LIVP-14 had the same HindIII endonuclease restriction map for its DNA and growth parameters in cell cultures as parental LIVP strain.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Route of Administration of the Vaccinia Virus Strain LIVP to Mice on Its Virulence and Immunogenicity

Щелкунов

Yakubitskiy

Сергеев

et al. 2020

Viruses

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The mass smallpox vaccination campaign has played a crucial role in smallpox eradication. Various strains of the vaccinia virus (VACV) were used as a live smallpox vaccine in different countries, their origin being unknown in most cases. The VACV strains differ in terms of pathogenicity exhibited upon inoculation of laboratory animals and reactogenicity exhibited upon vaccination of humans. Therefore, each generated strain or clonal variant of VACV needs to be thoroughly studied in in vivo systems. The clonal variant 14 of LIVP strain (LIVP-14) was the study object in this work. A comparative analysis of the virulence and immunogenicity of LIVP-14 inoculated intranasally (i.n.), intradermally (i.d.), or subcutaneously (s.c.) to BALB/c mice at doses of 108, 107, and 106 pfu was carried out. Adult mice exhibited the highest sensitivity to the i.n. administered LIVP-14 strain, although the infection was not lethal. The i.n. inoculated LIVP-14 replicated efficiently in the lungs. Furthermore, this virus was accumulated in the brain at relatively high concentrations. Significantly lower levels of LIVP-14 were detected in the liver, kidneys, and spleen of experimental animals. No clinical manifestations of the disease were observed after i.d. or s.c. injection of LIVP-14 to mice. After s.c. inoculation, the virus was detected only at the injection site, while it could disseminate to the liver and lungs when delivered via i.d. administration. A comparative analysis of the production of virus-specific antibodies by ELISA and PRNT revealed that the highest level of antibodies was induced in i.n. inoculated mice; a lower level of antibodies was observed after i.d. administration of the virus and the lowest level after s.c. injection. Even at the lowest studied dose (106 pfu), i.n. or i.d. administered LIVP-14 completely protected mice against infection with the cowpox virus at the lethal dose. Our findings imply that, according to the ratio between such characteristics as pathogenicity/immunogenicity/protectivity, i.d. injection is the optimal method of inoculation with the VACV LIVP-14 strain to ensure the safe formation of immune defense after vaccination against orthopoxviral infections.

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Antitumor effect of the LIVP-GFP recombinant vaccinia virus

Cited by 12 publications

References 10 publications

Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro

Oncolytic virus efficiency inhibited growth of tumour cells with multiple drug resistant phenotype in vivo and in vitro

Mutations in the <i>A34R</i> gene increase the immunogenicity of vaccinia virus

Effect of the Route of Administration of the Vaccinia Virus Strain LIVP to Mice on Its Virulence and Immunogenicity

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