SARS-CoV-2 proteins and anti-COVID-19 drugs induce lytic reactivation of an oncogenic virus.

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.

A promiscuous inflammasome sparks replication of a common tumor virus.

Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein-Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1-mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.

Anti-viral treatment and cancer control.

Hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), and Epstein-Barr virus (EBV) contribute to about 10-15 % global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infections have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell lymphotropic virus type 1 (HTLV-1) had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA-interference-based therapies for treating HPV-associated cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.

Role of the ubiquitin system and tumor viruses in AIDS-related cancer.

Tumor viruses are linked to approximately 20% of human malignancies worldwide. This review focuses on examples of human oncogenic viruses that manipulate the ubiquitin system in a subset of viral malignancies; those associated with AIDS. The viruses include Kaposi's sarcoma herpesvirus, Epstein-Barr virus and human papilloma virus, which are causally linked to Kaposi's sarcoma, certain B-cell lymphomas and cervical cancer, respectively. We discuss the molecular mechanisms by which these viruses subvert the ubiquitin system and potential viral targets for anti-cancer therapy from the perspective of this system. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Synthesis and antiviral evaluation of some new glycosylthioureas containing a quinazolinone nucleus.

A new synthesis of glycosylthioureas containing a quinazolinone nucleus is described utilizing per-O-acetylglycopyranosylisothiocyanates and several aminoquinazolinones as starting compounds. Structural proofs of these compounds are provided from elemental analyses, IR, 1H and 13C NMR spectra and mass spectra. The biological activity of these compounds has been studied.

L-Nucleoside analogues against cancer-causing viruses have potential in the prevention, delayed onset and treatment of viral associated cancers.

It has been established that several types of cancers have a strong association with viruses. Thus, a potent antiviral compound without toxicity upon long-term usage will be useful not only for the treatment of viral diseases but also for the prevention or the delayed onset of those cancers that have a strong association with viruses. These compounds, depending upon their mechanism of action, could also potentially be useful for the treatment of those viral-associated cancers. L(-)Deoxynucleoside analogues were discovered in my laboratory and by others as an important class of antiviral and anti-cancer chemical entities. L(-)SddC (3TC, lamivudine), L(-)FTC, L(-)Fd4C, and L(-)FMAU are compounds with potent activity against hepatitis B virus (HBV), but with different biological and pharmacological profiles. These compounds may be useful in the prevention or delayed onset of hepatocellular carcinoma associated with HBV. L(-)I-OddU is a potent anti-Epstein-Barr virus (EBV) compound without cytotoxicity and animal toxicity upon long-term dosing, which allows drug concentration in plasma that are much higher than those that are antivirally active. This compound may have the potential to prevent B-cell lymphoma associated with patients undergoing organ transplants in addition to its potential use for the treatment of EBV infection. Furthermore, it may also be useful for the treatment of EBV-associated cancers. In this manuscript, the metabolism, mechanism of action and the resistance, as well as the potential use of this class of compounds targetted against HBV, will be discussed.

Selenium interactions with carcinogens.

Although selenium was once considered to be a toxic, undesirable and carcinogenic element, it is now recognized as an essential element with anticarcinogenic properties. Epidemiological studies in the United States have shown an inverse relationship between selenium intake and certain forms of cancer in humans, but other factors must be considered since cancer is not higher in people living in selenium-deficient areas of the world (Finland, New Zealand, and Keshan disease area, China). Under most dietary conditions, selenium has been shown to reduce the spontaneous mammary tumor incidence in an inbred strain of mice. In general, selenium will counteract to various degrees, the chemical carcinogens used to produce lesions of the skin [coal tar, 3-methylcholanthrene, alpha-pyrene, and 7,12 dimethylbenz(a) anthracene (DMBA)], liver (3-methyl-4-dimethyl-aminoazobenzene, aflatoxin B1, and 2-acetylaminofluorene), mammary gland (DMBA and N-methyl-N-nitrosurea), and intestinal tract [1,2-dimethylhydrazine, bis(2-oxopropyl)nitrosamine, and azoxymethane]. Dietary factors, such as fat, will modify the protective effects of selenium. High dietary unsaturated fats, for example, markedly increase the mammary tumors in rats treated with DMBA, and selenium will reduce the tumor incidence but not to the level of rats fed a low fat diet. Other factors known to affect the anticarcinogenic effects of selenium include synthetic antioxidants, vitamin E, vitamin A and ascorbic acid. The mechanisms of selenium counteraction of carcinogens remain unknown.

Mode of regulation of natural killer cell activity by interferon.

Whereas xenogeneic tumors such as baby hamster kidney or HeLa cells grow in nude mice, the same cells persistently infected with a variety of viruses are rejected. Spleen cells from normal nude mice were found to be induced to produce interferon and to exert natural killer (NK) activity on virus persistently infected (PI) tumor cells, and not on uninfected parental cells in vitro. The phenotype of the interferon-producing cells and the NK effector cells was found to be the same namely, Qa 5(+), Ly 5(+), ganglio-N- tetraosylceramide, with 35 percent of the NK cells also expressing Thy 1.2. NK activity against virus PI tumor cell lines could be nonspecifically augmented both in vivo and in vitro by prior contact with virus PI tumor cells. It was unambiguously demonstrated with chemically homogeneous mouse interferon that interferon, and not a contaminant, was responsible for the augmentation of NK activity in vitro. Studies on the mode of interferon action in augmenting NK activity revealed that the target cell for interferon action was serologically distinct from the NK effector cell. Anti-Ly 5 + complement (C)-treated spleen cells were depleted of NK activity and the ability to produce interferon, but, upon incubation with interferon for 1-3 h, regained both NK activity and susceptibility to anti-Ly 5 + C. Treatment with anti-Qa 5 + C eliminated NK activity, which could not be restored by the addition of interferon. We conclude that interferon produced by Ly 5(+) cells in response to virus PI tumor cells acts on Ly 5(-) precursor cells and induces their differentiation into functional Ly 5(+) NK effector cells.

Interferons: rationale for clinical trials in neoplastic disease.

Interferons, cell glycoproteins synthesized in response to viral infections and various nonviral inducers, have proved therapeutically effective for viral infections in experimental models and in humans. Current evidence suggests interferons may also prove effective as antitumor agents in humans. Potent effects on cellular function result from interferons. Cell surface structure and enzyme levels are altered. Immunologic responses thought to be important in tumor immunity are augmented. Interferons have antiproliferative effects on the replication of normal and neoplastic cells. Interferons are effective in animals against tumors of both viral and nonviral origin. Clinical trials in cancer have been limited by the availability and cost of human interferons. However, results in small numbers of patients have been encouraging. This paper review experimental and clinical findings regarding the rationale for use of interferons in neoplastic disease.

Criteria for selection of new analogs of antitumor antibiotics.

If a new analog of a known antitumor antibiotic is to justify interest, it must be demonstrated to possess either quantitative or qualitative superiority over the parent compound in pharmacologic, toxicologic, immunologic, tumor cytotoxic, or other biologic properties that are therapeutically favorable. The most commonly used criterion is in vivo activity in are therapeutically favorable. The most commonly used criterion is in vivo activity in experimental tumor systems. This may be demonstrated in primary screening systems or in secondary screening systems, or in refractory tumor systems, or in one or more tumors of a human xenograft panel. Data on adriamycin and bleomycin analogs give evidence of some of these approaches. An additional criterion for selection of analogs involves the demonstration of a broader spectrum of effectiveness against a panel of experimental systems. Actinomycin D is used as an exampled. There are a variety of factors that may be employed in determining further clinical interest for analogs of known antitumor antibiotics. It is important to delineate the limiting characteristics in the clinical application of the parent antitumor antibiotic and to the choose the appropriate systems to identify and characterize new analogs and investigate them in depth in order to determine whether they may provide some advantage either in antitumor selectivity or in the diminution of host toxicity with retention of antitumor effectiveness.