The study of the etiology of cancer is critical to understanding how to prevent this disease and to improve treatment. In addition to genetic and environmental factors, several viruses also can trigger the development of cancer. Kaposi’s sarcoma-associated herpesvirus (KSHV), also referred to as human herpesvirus-8 (HHV-8), is one the few viruses proven to be associated with tumorigenesis in humans. It is causally associated with all clinical and epidemiological variants of Kaposi’s sarcoma (KS), a complex multifocal neoplasm characterized by proliferation of spindle-like cells, substantial angiogenesis, and inflammation. KS is found frequently in AIDS patients and now represents the most common cancer in certain parts of Africa. KS also occurs in transplant recipients residing in those countries where KSHV infection is common. Of note, in Israel, the incidence rate of the classic KS variant, which mostly occurs in elderly men, is one of the highest in the developed world; accordingly, relatively high infection rates of 10-13% were found in the Jewish Israeli population. KSHV is also involved in the pathogenesis of two lymphoproliferative disorders: primary effusion lymphoma (PEL) and a subset of multicentric Castleman’s disease (MCD). While the virus is important from clinical and public health standpoints, it also provides a source of basic information on how viruses might induce cellular proliferation and transformation. This may also offer clues for the understanding of normal and tumorigenic signal transduction pathways.
Exploring the Cellular and Viral Pathways of KSHV Infection Cycle and Pathogenesis
Like all other herpesviruses, primary infection with KSHV is followed by a lifelong latent infection, with the potential for virus reactivation, leading to an increased risk for disease development. Host factors and signal transduction pathways that play a role in KSHV infection and lytic reactivation have not been fully elucidated. Sarid's group studies the cellular and viral signaling pathways that allow productive infection, establishment of long-term latent infection and switch KSHV infection from the latent to the lytic life cycle.
In addition, by examining viral gene expression, viral-host protein interactions, and the effect of viral proteins on cell proliferation, cell death, and signal transduction pathways, Sarid's lab is characterizing the function and regulation of selected viral genes and their protein products that are potentially involved in the pathogenesis of KSHV.
Knowledge of the function of viral proteins is expected to help clarify the cellular pathways involved not only in KSHV-related cancers but cancer in general.
KSHV: Clinical and Epidemiological Studies
A number of clinical and epidemiological aspects related to KSHV have been under investigation in Sarid's laboratory. These include determination of the prevalence of KSHV infection in the Israeli population, determination of the transmission routes of KSHV, identification of unique clinical cases associated with KSHV infection, characterization of the infection status of KSHV during organ transplantations, and assessment of selected biological correlates as markers for disease progression. Currently, unique cases, involving the infection with KSHV, are being investigated.
Drug Discovery, Design and Delivery Research for Infectious Disease
In collaboration with Prof. Aharon Gedanken, Sarid’s team has generated composite nanoparticles for the inhibition of viral infection. Specifically, silver and gold nanoparticles capped with mercaptoethane sulfonate were synthesized through a sonication-based technique.
These nanoparticles were shown to mimic heparan sulfate (HS), a molecule that serves as a cellular receptor for a number of viruses, including the herpes simplex virus type 1 and HIV.
So far, Sarid's and Gedanken’s compound has been shown to block infection by HSV-1 as well as five different influenza viruses. Mechanistic studies revealed that the nanoparticles interfere with HSV-1 attachment, entry, and cell-to-cell spread, thereby preventing subsequent viral infection in a multimodal manner.
The ligand multiplicity achieved with carrier nanoparticles is crucial for generating polyvalent interactions with the virus at high specificity, strength and efficiency. This multivalent nanoparticles-mediated inhibition route is a promising approach for alternative antiviral therapy.