An Overview of Bacterial and Viral Inhibitors Involved in Gene Therapy of Hepatocellular Carcinoma (Hcc)

Hepatocellular carcinoma (HCC) is a form of cancer that is very widespread around the world and has a high mortality rate. Extensive evidence suggests that, HCC is a multifactorial disease. Hepatic cirrhosis is present, along with systemic inflammation and viral infections such as hepatitis B or C. Thus, giving rise to genetically and phenotypically heterogeneous hepatocellular carcinoma tumors. Researchers have found that bacterial and viral inhibitors can be used to silence targeted genes in hepatocellular carcinoma. Many bacterial species such as; Salmonella, Listeria, and Escherichia, proved to have anti-tumor properties. Up till now, adenoviral, retroviral, herpes-simplex viral and adeno-associated viral vectors have been modified and are being used for HCC gene therapy. In patients, up regulation of TLR signaling have also been observed showing an interesting influence on HCC’s microenvironment. TLR 4 and TLR 9 have positive relationship with tumor whereas, TLR3 is associated with anti-tumor influence. TLRs can cause an inflammatory response in the presence of foreign pathogens including bacteria and fungi. This review reflects an insight into the biology of HCC suggesting that certain signaling pathways and molecular alterations plays a very significant role in HCC development. As well as new experimental approaches, including; anti-angiogenesis, cancer therapy, oncolytic virotherapy, and suppressing the function of oncogenes, leading to apoptosis are successively being applied. The current challenge for the researchers is to identify a medicament which is selective for tumors specific cells only, having minimal noxiousness and harmless to normal tissue. We have scrutinized research articles based on how to merge viral and bacterial anticancer therapies into a single treatment for HCC.

A novel domain within the CIL regulates egress of IFITM3 from the Golgi and prevents its deleterious accumulation in this apparatus

The InterFeron-Induced TransMembrane proteins (IFITMs) are broad viral inhibitors that protect cells by preventing viral-to-cellular membrane fusion and they belong to the dispanin/CD225 family that includes vesicle trafficking regulators and proteins of unknown functions into four subfamilies (A-D). In this study, we uncover a novel domain that regulates the egress of IFITM3 from the Golgi and that is required to prevent IFITM3-driven v- to t-SNAREs membrane fusion inhibition and Golgi dysfunctions. The S-x-K-x-R-D domain is conserved among vertebrate members of the dispanin/CD225 A subfamily that regroups all IFITMs and through the study of mutations identified in patients affected by paroxysmal kinesigenic dyskinesia (PKD), we determine that it is functionally conserved also in PRRT2, member of the B subfamily. Overall, our study defines a novel domain that regulates the egress of dispanin/CD225 members from the Golgi and stresses the importance that regulation of this process bears to preserve the functions of this apparatus.

Direct Priming of CD8+ T Cells Persists in the Face of Cowpox Virus Inhibitors of Antigen Presentation

Vaccinia virus (VACV) was the vaccine used to eradicate smallpox and is being repurposed as a vaccine vector. CD8+ T cells are key anti-viral mediators, but require priming to become effector or memory cells. Priming requires an interaction with dendritic cells that are either infected (direct priming), or that have acquired virus proteins but remain uninfected (cross priming). To investigate CD8+ T cell priming pathways for VACV, we engineered the virus to express CPXV12 and CPXV203, two inhibitors of antigen presentation encoded by cowpox virus. These intracellular proteins would be expected to block direct but not cross priming. The inhibitors had diverse impacts on the size of anti-VACV CD8+ T cell responses across epitopes and by different infection routes in mice, superficially suggesting variable use of direct and cross priming. However, when we then tested a form of antigen that requires direct priming, we found surprisingly that CD8+ T cell responses were not diminished by co-expression with CPXV12 and CPXV203. We then directly quantified the impact of CPXV12 and CPXV203 on viral antigen presentation using mass spectrometry, which revealed strong, but incomplete inhibition of antigen presentation by the CPXV proteins. Therefore, direct priming of CD8+ T cells by poxviruses is robust enough to withstand highly potent viral inhibitors of antigen presentation. This is a reminder of the limits of viral immune evasion and shows that viral inhibitors of antigen presentation cannot be assumed to dissect cleanly direct and cross priming of anti-viral CD8+ T cells. Importance CD8+ T cells are key to anti-viral immunity, so it is important to understand how they are activated. Many viruses have proteins that protect infected cells from T cell attack by interfering with the process that allows virus infection to be recognised by CD8+ T cells. It is thought that these proteins would also stop infected cells from activating T cells in the first place. However, we show here that this is not the case for two very powerful inhibitory proteins from cowpox virus. This demonstrates the flexibility and robustness of immune processes that turn on the immune responses required to fight infection.