Chris Benedict

Associate Professor

My laboratory studies the strategies that viruses use to escape detection by our immune system, which help them to replicate in our cells and, in some cases, establish lifelong infections that we can never clear. We have a particular interest in those virus-employed tricks that target proteins of the tumor necrosis factor (TNF) family, as these proteins released by our immune cells are fundamentally important in promoting immunity. We have a particular interest in cytomegalovirus (CMV), which is a member of the herpesvirus family similar to ‘mono’ (Epstein-Barr) and the chicken pox (Varicella zoster) viruses. CMV encodes one of the largest viral genomes (~230,000 base pairs), and more than half of it is dedicated to throwing up smoke screens that fool our immune systems, including many that block the TNFs. We believe that studying the very unique CMV strategies that allow it to evade detection by our immune system facilitates fundamental new discoveries about our health. In addition, our lab is focused on finding new ways to combat the diseases that CMV can cause in certain settings. CMV is the No. 1 infectious cause of birth defects in the U.S. today, causing severe disease if immunity is naïve or compromised (e.g. infection of babies in the womb and transplant patients), and we are developing new vaccine strategies to combat this. If you have a healthy immune system, CMV infection is largely benign. However, like the chicken pox that can reemerge 50 years later to cause shingles, CMV ‘hides’ in your body for life and can pop-out again when your immune system is weakened or older. Consequently, CMV is a likely contributor to auto-inflammatory disorders such as vascular disease and immune senescence, and may even contribute to some cancers. One of our recent discoveries could aid efforts to in the development of a CMV vaccine.

 

 

 

 

Key Words: 

CMV epitopes, gene signature, genome-wide transcriptome, guinea pig, immune system, infection, interferon (IFN), mouse, rhesus macaque, simian immunodeficiency virus (SIV), T cell, tissue resident TRM, tumor necrosis factor (TNF), TRAIL, virus.

Dr. Benedict is an immunologist. His research team is focused on studying the strategies that persisting viruses use to evade the immune system and establish lifelong infections that cannot be cleared. They mainly study cytomegalovirus (CMV), a virus that infects the majority of Americans and is the #1 infectious cause of congenital birth defects in the USA.  Despite this high prevalence, most people haven’t even heard of CMV!!  CMV induces a very unique T cell response which commonly usurps >10% of all human T cells, and uncovering the mechanism(s) by which these are generated will help elucidate how persistent infection is controlled and also provide novel insights for vaccine development.  In this regard, CD4 T cells are of a particular interest for the Benedict lab. In addition, the lab studies the molecular antiviral signaling pathways initiated by cytokines – those of the tumor necrosis factor (TNF) and interferon (IFN) families. They discovered that CMV blocks signaling of TNF-related apoptosis inducing ligand (TRAIL), which is important in fighting off virus infections and has also been a major target for anti-cancer drug development. The CMV protein that helps in evading the response is UL141. Another CMV protein, UL144, is expressed in myeloid cells latently infected with HCMV, suggesting that it plays a key role in promoting CMV persistence. Although targeting UL141 & UL144 can be challenging for drug or vaccine development, the fact that the infectivity of CMV is severely crippled by neutralizing single immune modulatory gene merits further R&D.

Dr. Benedict has also identified the first CMV epitopes that are recognized by CD4 T cells in mice, and has recently shown that vaccination with these epitopes protects mice from CMV. Currently, it is primarily the large pharmaceutical companies (e.g. GSK, Pfizer) showing interest in pursuing vaccine development against CMV to the end stages, mainly because the design study for testing a CMV vaccine for protection against congenital infection will entail enrollment of nearly 10,000 patients (likely costing around $ 50 million), a daunting task for smaller companies. The main thrust behind the research is to understand how we can harness the T cells for clinical gain. At present there are mouse, guinea pig and rhesus macaque CMV infection models. Recently, it has been demonstrated by other groups (Picker lab, OHSU) that vectors built upon a CMV-backbone elicit strong tissue resident effector memory T cell responses which can control simian immunodeficiency virus (SIV) early infection. These cells maintain high frequencies for long times. One of Dr. Benedict’s long-term research goals is to purify T cells, extract RNA and perform single cell sequencing analysis to assess at the genome-wide transcriptome level the differences between T cells that are effective at protecting against CMV, and those that are not.

The work is preclinical and Dr. Benedict would like to provide expertise to the companies by evaluating their vaccines candidates to test whether they elicit an effective T cell response, based on gene signatures. He routinely collaborates with pharmaceutical companies both big and small.  

Although defining Tcell response signature has been done in mice for more active and ongoing industry collaborations Dr. Benedict recognizes that it is important to demonstrate the same in humans. Dr. Benedict supports having a report where research information, industry contacts etc. is readily available to the vaccine research community in the VEC and at LJI.

Dr. Benedict collaborates actively with many labs within LJI, including those of Mitchell Kronenberg, Bjoern Peters, Alex Sette, Sonia Sharma, Mick Croft, Dirk Zajonc, Steve Schoenberger, Klaus Ley and Lynn Hedrick.  He also has many active collaborations with researchers at UCSD and beyond, including joint publications and grants.

More information about Dr.Benedicts works can be found here: 

https://www.lji.org/faculty-research/labs/benedict/#overview