The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which is the causative pathogen for the coronavirus disease 2019 (COVID‐19) pandemic, has greatly stressed our healthcare system. In addition to severe respiratory and systematic symptoms, several comorbidities increase the risk of fatal disease outcomes, including chronic viral infections. Increasing cases of lytic reactivation of human herpesviruses in COVID‐19 patients and vaccinated people have been reported recently. SARS‐CoV2 coinfection, COVID‐19 treatments, and vaccination may aggravate those herpesvirus‐associated diseases by reactivating the viruses in latently infected host cells. In this review, we summarize recent clinical findings and limited mechanistic studies regarding the relationship between SARS‐CoV‐2 and different human herpesviruses that suggest an ongoing potential threat to human health in the postpandemic era.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, through simultaneously inhibiting Myc and HIF1α expression. Echinomycin treatment also induces viral lytic gene expression whereas not increasing infectious virions production from KSHV + tumor cells. Our comparative transcriptomic analysis has identified a bunch of new Echinomycin-regulated, Myc- and HIF1α-related genes contributed to KSHV pathogenesis, including KDM4B and Tau, which are required for the survival of KSHV + tumor cells with functional validation. These data together reveal that dual targeting Myc and HIF1α such as using Echinomycin may represent a new and promising option for treatments of these virus-associated malignancies.

ObjectiveKaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown.MethodsIn the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis.ResultsWe reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture.ConclusionOur data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases.

Although Kaposi’s sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus–host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis.