Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body’s immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy.
236 Background: The upregulated expression of CXCL1 has been validated in colorectal cancer patients. As a potential biotherapeutic target for colorectal cancer, the mechanism by which CXCL1 affects the development of colorectal cancer is not clear. Methods: Expression data of CXCL1 in colorectal cancer were obtained from the GEO database and verified using the GEPIA database and the TIMER 2.0 database. Knockout and overexpression of CXCL1 in colorectal cancer cells by CRISPR/Cas and "Sleeping Beauty" transposon-mediated gene editing techniques. Cell biological function was demonstrated by CCK-8, transwell chamber and Colony formation assay. RT-qPCR and Western Blot assays measured RNA and protein expression. Protein localization and expression were measured by immunohistochemistry and immunofluorescence. Results: Bioinformatics analysis showed significant overexpression of CXCL1 in the colorectal cancer tissues compared to normal human tissues, and identified CXCL1 as a potential therapeutic target for colorectal cancer. We demonstrate that CXCL1 promotes the proliferation and migration of colon cancer cells and has a facilitative effect on tumor angiogenesis. Furthermore, CXCL1 elevation promoted the migration of M2-tumor associated macrophages (TAMs) while disrupting the aggregation of CD4+ and CD8+ T cells at tumor sites. Mechanistic studies suggested that CXCL1 activates the NF-κB pathway. In the in vivo colon cancer transplantation tumor model, treatment with the P300 inhibitor C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer. Conclusions: CXCL1 promotes colon cancer development through activation of NF-κB/P300, and that CXCL1-based therapy is a potential novel strategy to prevent colon cancer development.
Upon HSV-1 infection, viral protein 16 (VP16), supported by Host Cell 21 Factor C1 (HCFC1), is rapidly transported into the nucleus, and help to express a series 22 of HSV-1 immediate-early proteins to begin its lytic replication. However, no direct 23 evidence has shown if the HCFC1 deficiency can affect the proliferation of HSV-1 so far. 24 Here, we showed that the HCFC1 deficiency led to a strong resistance to HSV-1 infection. 25 Moreover, we identified Host Cell Factor C1 Regulator 1 (HCFC1R1) as a new host 26 factor acting early in HSV infection for the transport of the HSV-1 capsid to the nucleus. 27 The HCFC1R1 deficiency also led to a strong resistance to HSV-1 infection. The 28 HCFC1R1 deficiency did not affect the attachment of HSV-1 to host cells but act early in 29 HSV-1 infection by perturbing the formation of HCFC1/VP16 complex. Remarkably, in 30 addition to wild-type HSV-1 infection, the host cells in the absence of either HCFC1 or 31 HCFC1R1 showed strong resistant to the infection of TK-deficient HSV-1, which strain 32 can course severe symptoms and tolerate to the current anti-HSV drug Acyclovir. Our 33 data suggest that HCFC1 or HCFC1R1 may be used as the novel target for developing 34 anti-HSV-1 therapies. 35IMPORTANCE Herpes simplex virus-1 (HSV-1) is widely spread in the human 36 population and can cause a variety of herpetic diseases. Acyclovir, a guanosine analogue 37 that targets the TK protein of HSV-1, is the first specific and selective anti-HSV-1 drug. 38However, the rapid emergence of resistant HSV-1 strains is occurring worldwide, 39 endangering the efficacy of Acyclovir. Alternatively, targeting host factors is another 40 strategy to stop HSV-1 infection. Unfortunately, although the HSV-1's receptor, 41 was discovered in 1998, no effective antiviral drug to date has been developed by 42 targeting Nectin-1. Targeting multiple pathways is the ultimate choice to prevent HSV-1 43 infection. Here we demonstrated that the deletion of HCFC1 or HCFC1R1 exhibits a 44 strong inhibitory effect on both wild-type and TK-deficient HSV-1. Overall, we present 45 evidence that HCFC1 or HCFC1R1 may be used as the novel target for developing 46 anti-HSV-1 therapies with a defined mechanism of action. 47 Key Words: Herpes simplex virus; HCFC1R1; VP16; HCFC1;HSV-1 48 49 50 51 52 53 54 55 3Herpes simplex virus 1 (HSV-1) is a member of the alphaherpesvirus family, which can 56 establish both lytic and latent infection (1, 2). Upon HSV-1 infection, HSV glycoprotein 57 B or C mediates viral adhesion by binding to heparan sulfate proteoglycans on the cell 58 surface, followed by HSV glycoprotein D interacting with Nectin-1, HVEM, and 59 3-O-sulfated heparan sulfate (3-5). For the viral genome that replicates in the nucleus, the 60 viral entry also entails the extensive movement of viruses passing through the cytoplasm. 61In this context, the capsid of HSV-1 may be transported to the nuclear pore complex 62 (NPC) through a vascular bundle since electronic microscopy analysis has shown 63 ne...
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