Herpes Simplex Virus Type‐1 (HSV‐1) Entry into Human Mesenchymal Stem Cells Is Heavily Dependent on Heparan Sulfate

Choudhary, Samiksha; Marquez, Maribel; Alencastro, Frances; Spors, Frank; Zhao, Yuanxiang; Tiwari, Vaibhav

doi:10.1155/2011/264350

Cited by 37 publications

(25 citation statements)

References 44 publications

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“…Likewise, the cell surface expression of nectin-2 by SK-N-SH, which we expected to be high based on qRT-PCR, was instead only moderate. Despite the high level of 3-OS HS in most neuroblastoma lines in the panel, we only detected relatively low levels of heparan sulfate 3- O -sulfotransferase 3 (HS3ST3), which previous studies used as an surrogate marker for 3-OS HS ( 10 , 16 , 17 ), indicating that other heparan sulfate 3- O -sulfotransferase isoforms ( 18 ) might be responsible for this receptor expression on neuroblastoma cells. We also mined the Pediatric Preclinical Testing Program (PPTP) gene expression database and found that most neuroblastoma xenograft tumors in that panel express relatively high levels of nectin-1 ( Supplementary Figure S4 , yellow columns, mRNA Z-score > 0) at the RNA level compared to other pediatric cancer models in the panel.…”

Section: Resultscontrasting

confidence: 63%

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Swain

Kunkler

et al. 2015

Gene Ther

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Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is less than 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic HSV, Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

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Section: Resultscontrasting

confidence: 63%

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Swain

Kunkler

et al. 2015

Gene Ther

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“…MSCs originated from bone marrow have been shown to be permissive to HSV-1 [43], while heparan sulfate has been suggested as a major determinant for virus entry in adipose tissue derived MSC [73]. To investigate the degree of permissivity of FM-MSCs to HSV-1 and HSV-2, monolayers of FM-MSCs were infected with a clinical isolate of HSV-1, or the HSV-2 laboratory strain G. When infected cells were observed under an optical inverted microscope, the typical HSV-induced cpe became apparent from 16–24 h pi at high moi (1A), whereas cpe was observable only at later times after infection at low moi.…”

Section: Resultsmentioning

confidence: 99%

Susceptibility of Human Placenta Derived Mesenchymal Stromal/Stem Cells to Human Herpesviruses Infection

et al. 2013

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Fetal membranes (FM) derived mesenchymal stromal/stem cells (MSCs) are higher in number, expansion and differentiation abilities compared with those obtained from adult tissues, including bone marrow. Upon systemic administration, ex vivo expanded FM-MSCs preferentially home to damaged tissues promoting regenerative processes through their unique biological properties. These characteristics together with their immune-privileged nature and immune suppressive activity, a low infection rate and young age of placenta compared to other sources of SCs make FM-MSCs an attractive target for cell-based therapy and a valuable tool in regenerative medicine, currently being evaluated in clinical trials. In the present study we investigated the permissivity of FM-MSCs to all members of the human Herpesviridae family, an issue which is relevant to their purification, propagation, conservation and therapeutic use, as well as to their potential role in the vertical transmission of viral agents to the fetus and to their potential viral vector-mediated genetic modification. We present here evidence that FM-MSCs are fully permissive to infection with Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Varicella zoster virus (VZV), and Human Cytomegalovirus (HCMV), but not with Epstein-Barr virus (EBV), Human Herpesvirus-6, 7 and 8 (HHV-6, 7, 8) although these viruses are capable of entering FM-MSCs and transient, limited viral gene expression occurs. Our findings therefore strongly suggest that FM-MSCs should be screened for the presence of herpesviruses before xenotransplantation. In addition, they suggest that herpesviruses may be indicated as viral vectors for gene expression in MSCs both in gene therapy applications and in the selective induction of differentiation.

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“…Cell surface carbohydrates can affect virus entry at the stage of virion attachment, but the importance of this interaction varies among viruses and cells. For example, sialic acid is thought to be sufficient for influenza virus attachment and entry, while the role of GAGs during HSV-1 entry is more complex (41,46,47). The herpesviruses are thought to first engage heparan sulfate on the surface of cells before engaging specific receptors (48).…”

Section: Discussionmentioning

confidence: 99%

A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection

Riblett

Blomen

Jae

et al. 2016

J Virol

110

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Rift Valley fever virus (RVFV) causes recurrent insect-borne epizootics throughout the African continent, and infection of humans can lead to a lethal hemorrhagic fever syndrome. Deep mutagenesis of haploid human cells was used to identify host factors required for RVFV infection. This screen identified a suite of enzymes involved in glycosaminoglycan (GAG) biogenesis and transport, including several components of the cis-oligomeric Golgi (COG) complex, one of the central components of Golgi complex trafficking. In addition, disruption of PTAR1 led to RVFV resistance as well as reduced heparan sulfate surface levels, consistent with recent observations that PTAR1-deficient cells exhibit altered Golgi complex morphology and glycosylation defects. A variety of biochemical and genetic approaches were utilized to show that both pathogenic and attenuated RVFV strains require GAGs for efficient infection on some, but not all, cell types, with the block to infection being at the level of virion attachment. Examination of other members of the Bunyaviridae family for GAG-dependent infection suggested that the interaction with GAGs is not universal among bunyaviruses, indicating that these viruses, as well as RVFV on certain cell types, employ additional unidentified virion attachment factors and/or receptors. IMPORTANCE Rift Valley fever virus (RVFV) is an emerging pathogen that can cause severe disease in humans and animals. Epizootics among livestock populations lead to high mortality rates and can be economically devastating. Human epidemics of RiftValley fever, often initiated by contact with infected animals, are characterized by a febrile disease that sometimes leads to encephalitis or hemorrhagic fever. The global burden of the pathogen is increasing because it has recently disseminated beyond Africa, which is of particular concern because the virus can be transmitted by widely distributed mosquito species. There are no FDA-licensed vaccines or antiviral agents with activity against RVFV, and details of its life cycle and interaction with host cells are not well characterized. We used the power of genetic screening in human cells and found that RVFV utilizes glycosaminoglycans to attach to host cells. This furthers our understanding of the virus and informs the development of antiviral therapeutics. R ift Valley fever virus (RVFV) is a member of the Bunyaviridae family of viruses that cause emerging infections that threaten both human and livestock populations on several continents (1).Bunyaviruses have a tripartite, negative-sense RNA genome and are frequently transmitted by insects (1). RVFV can be transmitted by mosquitoes or by exposure to infected tissues and body fluids and is considered endemic in much of Africa (2). In humans, RVFV can cause an acute fever leading to complications such as kidney failure and, in about 1% of cases, a lethal hemorrhagic fever (3, 4). In addition, RVFV spreads rapidly across infected herds of livestock and can cause significant mortality in infected animals (5, 6).We t...

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Herpes Simplex Virus Type‐1 (HSV‐1) Entry into Human Mesenchymal Stem Cells Is Heavily Dependent on Heparan Sulfate

Cited by 37 publications

References 44 publications

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Susceptibility of Human Placenta Derived Mesenchymal Stromal/Stem Cells to Human Herpesviruses Infection

A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection

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