Human Immunodeficiency virus (HIV)
Approximately 33 million people currently live with HIV, the causative agent of acquired immune deficiency syndrome (AIDS), with an annual death toll of about 2 million people. No prophylactic vaccine is available to prevent a further 2.7 million annual new infections. Despite the clear therapeutic advances of highly effective anti-retroviral drug combinations, no treatments exist to clear HIV infection. A small population of infected cells serves as a reservoir for dormant virus that avoids clearance by the immune system and has not been susceptible to any available drug treatment. Patients are thus left exposed to side effects from costly continuous life-long therapy, which also promotes the emergence of drug-resistant HIV strains. Understanding how host cellular factors regulate HIV replication and gene expression during productive infection and the switch to and from latency is key in combating HIV. At the Morgridge Institute we direct our efforts to identify viral and host targets that can be developed into new therapies that either prevent virus reactivation, or stimulate reactivation for subsequent virus clearing by the immune system or existing drug regimens.
About 15-20 percent of cancers are associated with virus infections. As a single cancer risk factor, the human papillomavirus (HPV) is arguably only second to smoking, causing essentially all cervical cancers, up to 25% of cancers of the head and neck, and a number of other cancers. Our studies utilize unique opportunities provided by cervical cancer screening programs to study all stages in the development of a human cancer. The results are and continue to be highly informative about the molecular mechanisms that drive human cancer progression, and have important implications for disease management, diagnosis and prognosis. The results inform the direction of mechanistic studies of cancer development in laboratory models and provide leads to develop clinical disease biomarker tests and identify targets for cancer therapy.
The Virology Team uses several model virus systems to study virus biology. We often use not particularly harmful viruses, selected for particularly high productivity in genetic and biochemical studies, which combine features that are also common among more dangerous viruses. Two of our virus model systems are based on plant bromoviruses and insect nodaviruses, which we have used to develop widely applicable methods to genetically manipulate and engineer RNA viruses, thus enabling many fundamental studies and practical applications. Among the advances are the first systematic, genome-wide identification of host genes that affect the replication of a virus, and the identification and characterization of novel intracellular organelles or factories that many viruses generate to replicate their genomes.
Other results on viral gene structure and function also imply that three broad classes of viruses, together representing half of known virus types, likely evolved from a common ancestor. The three groups of viruses include the positive-strand RNA viruses, which cause diseases from the common cold to liver cancer; retroviruses such as HIV; and double-stranded RNA viruses such as rotavirus, a leading killer of young children.
Systems Biology and Computation
The Virology Team has adopted a systems biology approach that includes the capture and analysis of data from interactions among thousands of genes, cells and proteins. The work requires integration of molecular genetics, genomics, biochemistry, cell biology and computational biology to address fundamental questions about how tiny viruses manage to escape detection and invade host cells. Systems biology requires vast computational capacity to handle the millions of possible permutations and outcomes, but offers major advantages over traditional approaches that focus on individual genes, cells and protein interactions.