Adenovirus vectors are one of the most frequently used vector systems in human clinical trials aimed at treating cancer and genetic diseases. Despite many advantages of adenovirus as a potential therapeutic, host immune responses to this viral vector remain a serious barrier to clinical applications. Intravascular delivery of adenovirus triggers hepatotoxicity and potent systemic inflammation. Both the adaptive and innate arms of the immune system are involved in rapid clearance of adenovirus. Together with our collaborator, Dr. Dmitry Shayakhmetov at Emory University, we are pursuing structural studies to guide engineering of adenovirus vectors that evade host immune responses. A recently designed virus, Ad5-3M, has targeted mutations in multiple capsid proteins and has been tested in mouse models of localized and disseminated lung cancer. Compared to wild-type adenovirus, Ad5-3M is better at both resisting inactivation by blood factors and avoiding sequestration in liver macrophages. In addition, Ad5-3M fails to trigger hepatotoxicity after intravenous delivery.
We are utilizing cryo-electron microscopy (cryo-EM) single particle reconstruction and tomography techniques to study engineered adenovirus vectors and adenovirus complexed with host immune molecules. The long term goal is to understand the molecular mechanisms underlying viral activation of systemic inflammation.
PI: Phoebe Stewart, Ph.D.