Paper of the Month: Crippled cytomegalovirus continues to provoke the immune system

PLoS PathogensThis month's featured paper is from the Hill lab, and is titled, Sustained CD8+ T Cell Memory Inflation after Infection. It was published in PLoS Pathogens.

The research in this paper was conducted as part of an investigative collaboration.*

Cytomegalovirus (CMV) is a common virus in the herpesvirus family that establishes lifelong infection in at least 50 percent of Americans. Although CMV causes disease in people with impaired immunity, the vast majority of infected people have no symptoms from this harmless virus.

Beneath the surface calm, however, CMV has a striking impact. Close to 10 percent of T cells in normal people are devoted to fighting CMV: a phenomenon that has been called “memory inflation.” It has generally been assumed that the body devotes this number of T cells to fighting CMV because CMV is constantly active, maintaining a low-grade “smoldering” infection.

Dr. Stenzel-Poore

"This paper provides an especially beautiful example of how new discoveries about the basic biology of viruses can lead to promising therapeutics for humans--in this instance, powerful new vaccine strategies."

This month’s paper published by the Ann Hill Lab challenges that view. Ann Hill, PhD, Chris Snyder, PhD, and colleagues report that a CMV mutant that cannot ever spread from the very first cells it infects on entering the body can still drive large “inflationary” T cell responses.

“There is something about CMV that drives the immune system absolutely nuts,” said Ann Hill, PhD, Professor, Department of Molecular Microbiology & Immunology, and senior author of the paper. “We have always been struck by how hard it is for us to find any evidence of virus activity, while the immune system appears to be screaming that it is seeing virus all the time. We wanted to understand how CMV keeps the immune system in this state of high alert. We assumed that it had to mean that somewhere in the body, tiny bursts of infection were occurring, even if they were rapidly extinguished by the immune system.”

As part of the experimental design, Dr. Hill’s team used two different systems to completely prevent virus spreading to infect a new cell. They inserted the HSV thymidine kinase gene into CMV to make it sensitive to the drug famcycolovir, and treated infected mice with famcyclovir to prevent virus replication. They also obtained a mutant virus that is genetically incapable of spreading from the cell it first infects. These two systems were intended to be negative controls: it was expected that memory inflation could not occur if virus infection were completely quenched. Strikingly, however, the team observed large inflationary T cell responses in both cases. The T cells still had an “effector” phenotype, which indicates that they have seen the virus recently.

The team’s data suggest that CMV can remain active and continuously stimulate the immune system, while avoiding immune-mediated clearance, without the capacity to spread from cell to cell. Furthermore, a rather tiny number of infected cells seem able to do this.

Ann Hill, PhD“This is important for two reasons” said Dr. Hill. “First, it means that CMV is able to hide in the body in a very special way. Most viruses that establish lifelong infections try to make themselves invisible to the immune system. CMV seems to be doing just the opposite. Second, we think that this result has exciting translational implications. CMV that cannot spread from the cells it first infects is completely harmless, even in animals that totally lack an immune system. We can use these crippled viruses as very safe vaccines.”

Louis Picker, MD, and colleagues in the OHSU Vaccine & Gene Therapy Institute and the Oregon National Primate Research Center have used CMV to create a vaccine that shows enormous promise for AIDS, reported earlier this year in a prominent Nature article.

“Our results suggest that Dr. Picker might be able to get away with making a vaccine that has no potential for harm, but could still achieve the immunity he wants,” said Dr. Hill. 

Dr. Hill’s lab is testing the idea that CMV could be used to express cancer antigens to make a cancer vaccine. “Because cancer treatment can severely suppress the immune system, we really needed a crippled CMV that would work,” she said. “It’s interesting that we didn’t start this work with any translational goal in mind; this was pure curiosity-driven basic science research. Yet the results have turned out to have enormous translational potential.”

Pictured: Ann Hill, PhD

Paper Authors

Christopher Snyder, PhD (3)
Kathy Cho, PhD (1)
Elizabeth Bonnett (1)
Jane  Allan (2)
Ann Hill, PhD (1)

Author Information

1 - Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, United States of America
2 - School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
3 - Dept. Microbiology & Immunology, Thomas Jefferson University, Philadelphia


The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.

This paper was selected because it provides an especially beautiful example of how new discoveries about the basic biology of viruses can lead to promising therapeutics for humans--in this instance, powerful new vaccine strategies