RR:C19 Evidence Scale rating by reviewer:
Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.
SARS-CoV-2 infection and COVID-19 pandemic have the potential to impact human health in unsuspected ways. Virally-induced cancers caused by human oncogenic viruses can be increased by certain co-founding microbial infections, including P. Falciparum and HIV-1. At the same time, the repurposing of FDA-approved drugs with the benefit of curtailing SARS-CoV-2 infection, and COVID-19 symptoms could also entail the risk of impacting the biology of human oncoviruses. In this interesting pre-print, Z. Qin and collaborators study the potential of SARS-CoV-2 proteins and COVID-19 drugs to increase the replication of Kaposi's sarcoma herpesvirus (KSHV/ HHV-8); an oncogenic virus implicated in Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL), two AIDS-related malignancies. The increase of KS in HIV/AIDS patients and transplant immunosuppression, together with the fact that antiretroviral therapy and immune reconstitution lead to AIDS-KS remission, suggest that KSHV replication and reactivation are necessary for the development of KS. Moreover, much of the KSHV oncogenic arsenal comprises genes expressed during the lytic phases that are immunogenic and under immune control. In this brief report by the Z. Qin group, laboratory-based KSHV replication systems and KSHV infected malignant PEL cells are used to show that the spike protein (S) and the nucleocapsid protein (N) of SARS-CoV-2, as well as some of the drugs being used for COVID-19, have the potential to reactivate KSHV. Researchers use the iSLK KSHV latent and lytic reporter system and PEL cells to show that ectopic expression of S or N viral genes can upregulate lytic gene expression. Using the same systems, they show that two drugs employed to treat COVID-19 patients, the antibiotic Azithromycin and the serine protease inhibitor Nafamostat mesylate, can induce lytic reactivation and exacerbate virus production. Mechanistically they provide additional data indicating that the ERK and NFkB signaling mediators may be involved in the drug effects. All these results have to be expanded and confirmed and therefore interpreted with caution. Many of the observed effects are modest and need to be fully quantified. Data on viral reactivation by SARS-CoV-2 genes needs to be expanded to show the upregulation of actual viral late lytic genes and KSHV virions' production using also natural KSHV infection systems. In the drugs' case, the results need to be confirmed by using primary infection systems. The ectopic expression of SARS-CoV-2 genes has to be complemented with studies using externally added proteins and; ideally, SARS-CoV-2 infection systems. Yet, the fact that SARS-CoV-2 can infect some of the cells infected by KSHV, such as vascular endothelial cells that also express the ACE2 receptor, suggests the plausibility of a co-infection scenario whereby SARS-CoV-2 infects a KSHV infected cell and affects its biology. Together with several reports showing that SARS-CoV-2 can exacerbate or cooperate with human herpesvirus infections such as EBV, these provocative results are important because they foster awareness of an underappreciated source of heightened oncogenic risk for the COVID-19 pandemic. They caution towards the need to focus more research on this important topic and to closely monitor KSHV-associated disease in people le that suffered COVID-19. This would apply to at-risk populations such as men who have sex with men and HIV/AIDS-affected individuals who recovered from COVID-19 infection, particularly those who underwent treatment with drugs with potential risk for KSHV reactivation.