Novel interventions for gammaherpesvirus infection and AIDS-Related Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

(Aim 1) To overcome current challenges in the development of herpesvirus vaccines, my collaborators and I devised a codon-shuffled complementing gene method to grow high titer replication-dead virus stocks. Building upon the success of this initial approach, we designed new recombinant viruses that inactivate other viral genes that are essential for latency of gammaherpesviruses. These new recombinant viruses function as an effective strategy to protect against wild-type virus challenge. We are comparing this attenuated, replication-dead and latency-defective virus vaccine candidate to administrations of glycoprotein-based antigens that overlap between MHV68, KSHV, and EBV. We also expanded our challenge approach to better model transmission in the human population, and we use imaging to track infection across tissues in live animals. (Aim 2) Immunotherapy is a rapidly expanding field to treat cancers. Small molecule inhibitors of a host molecule named cereblon block a type of protein modification called ubiquitination. Immunomodulatory agents including pomalidomide improves host control of infected cells and leads to resolution of KS in many patients. My lab has obtained mice that have a form of cereblon that is sensitive to pomalidomide. We have verified that these mice are permissive to infection in the absence of pomalidomide and will next evaluate the mechanistic impact of pomalidomide and related small molecule inhibitors on gammaherpesvirus infection using this new mouse model. (Aim 3) I continue to collaborate to help analyze the host immune response in the peripheral blood mononuclear cells of patients in HAMB clinical trials. We have used flow cytometry data to identify innate and adaptive immune responses that differ between patients that present with different KSHV diseases. This data was presented at scientific conferences and is in preparation for publication. (Aim 4) My laboratory is also collaborating with CAPR and LASP in ongoing studies to test if a small molecule inhibitor of host cyclin-dependent kinases outperforms the standard treatment of pegylated liposomal doxorubicin against controlling growth of KS patient-derived xenografts in NSG mice. We found that abemaciclib is not effective, likely involving the observed loss of the Retinoblastoma protein.