Sindbis viral vectors target hematopoietic malignant cells

Suzme, Raffi; Jc, Tseng; Levin, Brandi; Ibrahim, Sherif; Meruelo, Daniel; Pellicer, A.

doi:10.1038/cgt.2012.56

Cited by 9 publications

(7 citation statements)

References 49 publications

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“…Moreover, the mechanisms of protein synthesis directed by SINV mRNAs are helping to shed light on the structure-function relationship of viral mRNAs. From a practical viewpoint, SINV has been employed in fields as diverse as cancer therapy and has aided in the understanding of the adaptive antiviral response [ 8 , 9 ]. In the current review, we will summarize what is known about the mechanisms of translation of SINV mRNAs, with a focus on the initiation events of non-canonical translation of subgenomic mRNA (sgRNA).…”

Section: Introductionmentioning

confidence: 99%

The Regulation of Translation in Alphavirus-Infected Cells

Carrasco

Sanz

González-Almela

2018

Viruses

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Sindbis virus (SINV) contains an RNA genome of positive polarity with two open reading frames (ORFs). The first ORF is translated from the genomic RNA (gRNA), rendering the viral non-structural proteins, whereas the second ORF is translated from a subgenomic mRNA (sgRNA), which directs the synthesis of viral structural proteins. SINV infection strongly inhibits host cell translation through a variety of different mechanisms, including the phosphorylation of the eukaryotic initiation factor eIF2α and the redistribution of cellular proteins from the nucleus to the cytoplasm. A number of motifs have been identified in SINV sgRNA, including a hairpin downstream of the AUG initiation codon, which is involved in the translatability of the viral sgRNA when eIF2 is inactivated. Moreover, a 3′-UTR motif containing three stem-loop structures is involved in the enhancement of translation in insect cells, but not in mammalian cells. Accordingly, SINV sgRNA has evolved several structures to efficiently compete for the cellular translational machinery. Mechanistically, sgRNA translation involves scanning of the 5′-UTR following a non-canonical mode and without the requirement for several initiation factors. Indeed, sgRNA-directed polypeptide synthesis occurs even after eIF4G cleavage or inactivation of eIF4A by selective inhibitors. Remarkably, eIF2α phosphorylation does not hamper sgRNA translation during the late phase of SINV infection. SINV sgRNA thus constitutes a unique model of a capped viral mRNA that is efficiently translated in the absence of several canonical initiation factors. The present review will mainly focus in the non-canonical mechanism of translation of SINV sgRNA.

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Section: Introductionmentioning

confidence: 99%

The Regulation of Translation in Alphavirus-Infected Cells

Carrasco

Sanz

González-Almela

2018

Viruses

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“…However, no tumor targeting of luciferase expression was observed, suggesting that the natural targeting observed for SIN was not a common feature for alphaviruses [62]. Moreover, related to the SIN tropism, in contrast to earlier findings suggesting laminin receptors as targets for SIN, it was discovered that although JB leukemia cells express high levels of laminin receptors, they showed low susceptibility to SIN [63]. In another study, tumor tropism was investigated in a human ML-14a xenograft model, which indicated that SIN infections are not defined by the level of SIN receptors, but by interferon (IFN) response in tumors [64].…”

Section: Oncolytic Alphavirus Approachesmentioning

confidence: 99%

“…In addition to targeting solid tumors, SIN vectors were demonstrated to efficiently trigger apoptosis in murine BW5147 malignant hematopoietic T-cells [63]. In contrast, only modest efficacy was seen in human lymphoma and leukemia cells.…”

Section: Oncolytic Alphavirus Approachesmentioning

confidence: 99%

Oncolytic Alphaviruses in Cancer Immunotherapy

Lundström¹

2017

Vaccines

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Oncolytic viruses show specific targeting and killing of tumor cells and therefore provide attractive assets for cancer immunotherapy. In parallel to oncolytic viral vectors based on adenoviruses and herpes simplex viruses, oncolytic RNA viruses and particularly alphaviruses have been evaluated as delivery vehicles. Immunization studies in experimental rodent models for various cancers including glioblastoma, hematologic, hepatocellular, colon, cervix, and lung cancer as well as melanoma have been conducted with naturally occurring oncolytic alphavirus strains such as M1 and Sindbis AR339. Moreover, animals were vaccinated with engineered oncolytic replication-deficient and -competent Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus vectors expressing various antigens. Vaccinations elicited strong antibody responses and resulted in tumor growth inhibition, tumor regression and even complete tumor eradication. Vaccination also led to prolonged survival in several animal models. Furthermore, preclinical evaluation demonstrated both prophylactic and therapeutic efficacy of oncolytic alphavirus administration. Clinical trials in humans have mainly been limited to safety studies so far.

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“…Parvovirus B19[92] and sindbis[93] viruses have also been reported to exhibit oncolytic effects in hematologic malignancies, and further analyses for their clinical potential is needed.…”

Section: B Oncolytic Viruses and Applications In Hematological Maligmentioning

confidence: 99%

Gene and virotherapy for hematological malignancies

Domingo-Musibay

Yamamoto

2016

Int J Hematol

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Treatment of the hematological malignancies has undergone recent transformation. Advances in gene therapy and molecular techniques, as well as significant gains in computational abilities have supported rapid development of safer and better tolerated therapies for many patients with hematologic cancers. In this review, we discuss novel applications of gene therapy including immunomodulation and gene silencing, and report on the rise of oncolytic viruses to treat malignancies arising in cells of the blood, lymph, and marrow. We discuss the relationship of the tropism of wild-type viruses and their oncolytic behavior as well as tumoricidal and immunostimulatory properties of several attenuated and recombinant viruses in clinical development worldwide. While we have focused on promising virotherapy applications for future development, we also present a historical perspective and identify areas of potential clinical and regulatory practice change. Several of the virus systems being developed for hematogic application are outlined and efficacy data is summarized and presented in the context of ongoing or future human clinical testing. Advantages and limitations of gene and virus therapy are presented to readers including challenges and opportunities to improve treatment tolerability and outcomes for patients with hematologic malignancy.

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Sindbis viral vectors target hematopoietic malignant cells

Cited by 9 publications

References 49 publications

The Regulation of Translation in Alphavirus-Infected Cells

The Regulation of Translation in Alphavirus-Infected Cells

Oncolytic Alphaviruses in Cancer Immunotherapy

Gene and virotherapy for hematological malignancies

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