25-Hydroxycholesterol Inhibits Kaposi's Sarcoma Herpesvirus and Epstein-Barr Virus Infections and Activates Inflammatory Cytokine Responses.

Oncogenic gammaherpesviruses express viral products during latent and lytic infection that block the innate immune response. Previously, we found that Kaposi's sarcoma herpesvirus (KSHV/human herpesvirus-8) viral microRNAs (miRNAs) downregulate cholesterol biogenesis, and we hypothesized that this prevents the production of 25-hydroxycholesterol (25HC), a cholesterol derivative. 25HC blocks KSHV de novo infection of primary endothelial cells at a postentry step and decreases viral gene expression of LANA (latency-associated nuclear antigen) and RTA. Herein we expanded on this observation by determining transcriptomic changes associated with 25HC treatment of primary endothelial cells using RNA sequencing (RNA-Seq). We found that 25HC treatment inhibited KSHV gene expression and induced interferon-stimulated genes (ISGs) and several inflammatory cytokines (interleukin 8 [IL-8], IL-1α). Some 25HC-induced genes were partially responsible for the broadly antiviral effect of 25HC against several viruses. Additionally, we found that 25HC inhibited infection of primary B cells by a related oncogenic virus, Epstein-Barr virus (EBV/human herpesvirus-4) by suppressing key viral genes such as LMP-1 and inducing apoptosis. RNA-Seq analysis revealed that IL-1 and IL-8 pathways were induced by 25HC in both primary endothelial cells and B cells. We also found that the gene encoding cholesterol 25-hydroxylase (CH25H), which converts cholesterol to 25HC, can be induced by type I interferon (IFN) in human B cell-enriched peripheral blood mononuclear cells (PBMCs). We propose a model wherein viral miRNAs target the cholesterol pathway to prevent 25HC production and subsequent induction of antiviral ISGs. Together, these results answer some important questions about a widely acting antiviral (25HC), with implications for multiple viral and bacterial infections. IMPORTANCE A cholesterol derivative, 25-hydroxycholesterol (25HC), has been demonstrated to inhibit infections from widely different bacteria and viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its mechanism of activity is still not fully understood. In this work, we look at gene expression changes in the host and virus after 25HC treatment to find clues about its antiviral activity. We likewise demonstrate that 25HC is also antiviral against EBV, a common cancer-causing virus. We compared our results with previous data from antiviral screening assays and found the same pathways resulting in antiviral activity. Together, these results bring us closer to understanding how a modified form of cholesterol works against several viruses.

Intravenous Ketamine for Cancer Pain Management, Including Flares During the COVID-19 Pandemic: A Retrospective Study.

OBJECTIVES: Cancer-related neuropathic pain (CNP) affects an increasing proportion of cancer patients, given improved survival, but it remains difficult to treat. There are no studies on an extended intravenous ketamine protocol and its synergies with common neuropathy treatments to treat CNP. This study aims to 1) evaluate the safety and effectiveness of an intravenous ketamine protocol to treat refractory CNP and 2) uncover synergies between ketamine and common neuropathy treatments. METHODS: This is a single-center, retrospective review of 57 patients and 192 infusions, with prospective follow-up on 14 enrolled patients during the coronavirus disease 2019 (COVID-19) pandemic. RESULTS: The etiologies of CNP were as follows: 13 from tumor compression, 25 with chemotherapy-induced peripheral neuropathy, 13 from surgery, and 6 from radiation therapy. Overall, 42 of 57 patients (73.7%) were responders, and 71.8% of responders received >3 weeks of pain relief on their last infusion. Analysis of adjuvant treatments revealed that the combination of serotonin-norepinephrine reuptake inhibitors and ketamine resulted in an increase in responders compared with nonresponders (P < 0.01). Adverse events occurred in 32 of 192 infusions (16.7%). All side effects self-resolved or resolved with intervention per the adverse events protocol. During the pandemic, all 14 currently enrolled patients did not receive ketamine infusions. Thirteen of the 14 patients returned to baseline pain, with 61.5% increasing medications. All experienced worsened function, mobility, mood, or anorexia. CONCLUSION: Intravenous ketamine may be a safe and effective adjuvant treatment for CNP, especially with serotonin-norepinephrine reuptake inhibitors. Larger, prospective studies are warranted and should explore parameters to help prognosticate response to ketamine infusions.