The in vitro effect of SARS coronavirus 2 co-infection on lytic reactivation of an oncogenic herpesvirus

Abstract

The gamma-herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV) has oncogenic potential, particularly in immunosuppressed patients, and Kaposi’s sarcoma (KS) is the most common AIDS-related malignancy. KS is of particular significance in Sub-Saharan Africa, where both HIV and KSHV prevalence are high. KSHV displays a biphasic life cycle consisting of latent and lytic stages, and the lytic phase is associated with active virus replication and disease pathology. The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, presents an additional undetermined risk of cancer development, affecting already vulnerable populations. Recent clinical studies suggest that there may be potential interplay between SARS-CoV-2 infection and reactivation of opportunistic herpesvirus infections. The present study aimed to design an in vitro model for investigating the effects of SARS-CoV-2 co-infection on KSHV lytic reactivation. Vero E6 cells were stably infected with rKSHV allowing for the establishment of latency in the cells (Vero E6 rKSHV), with the potential for reactivation upon exposure to specific conditions. Vero E6 rKSHV cells were used to determine if infection with SARS-CoV-2 live virus, or infection with a pseudovirus bearing SARS-CoV-2 spike(S), or just SARS-CoV-2 S protein treatment alone could initiate KSHV lytic reactivation. Both live virus and pseudovirus infection of the latently infected cells was sufficient to induce KSHV lytic reactivation. Importantly, no reactivation was observed in response to a pseudovirus bearing an unrelated envelope protein. Direct treatment with S protein also did not produce the same effect. We speculate that the KSHV reactivation seen in this cell model was induced by an indirect S protein-mediated mechanism. The data gathered in this study contributes to the current understanding of KSHV lytic reactivation in the context of respiratory virus infection. While the underlying mechanisms require further investigation, this study provides evidence supporting the clinical observations of KSHV lytic reactivation in COVID-19 patients.