Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2.

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.

Co-Detection of EBV and Human Polyomavirus JCPyV in a Case of AIDS-Related Multifocal Primary Central Nervous System Diffuse Large B-Cell Lymphoma.

The human neurotropic Polyomavirus JCPyV is the widespread opportunistic causative pathogen of the fatal demyelinating disease progressive multifocal leukoencephalopathy; however, it has also been implicated in the oncogenesis of several types of cancers. It causes brain tumors when intracerebrally inoculated into rodents, and genomic sequences of different strains and expression of the viral protein large T-Antigen have been detected in a wide variety of glial brain tumors and CNS lymphomas. Here, we present a case of an AIDS-related multifocal primary CNS lymphoma in which JCPyV genomic sequences of the three regions of JCPyV and expression of T-Antigen were detected by PCR and immunohistochemistry, respectively. No capsid proteins were detected, ruling out active JCPyV replication. Sequencing of the control region revealed that Mad-4 was the strain of JCPyV present in tumor cells. In addition, expression of viral proteins LMP and EBNA-1 from another ubiquitous oncogenic virus, Epstein-Barr, was also detected in the same lymphocytic neoplastic cells, co-localizing with JCPyV T-Antigen, suggesting a potential collaboration between these two viruses in the process of malignant transformation of B-lymphocytes, which are the site of latency and reactivation for both viruses.

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas.

The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal-oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.