Paper of the Month: Research shows how virus evades immune systems
07/02/10 Portland, OR
This month's featured paper was published in the April edition of the journal Science, and is titled: "Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus."In the paper, Klaus Früh, PhD, Louis Picker, MD, and colleagues in the OHSU Vaccine & Gene Therapy Institute and the Oregon National Primate Research Center report on how a herpes virus called cytomegalovirus (CMV) continues to reinfect human hosts despite the body's capacity to control the primary infection.
Generally, the human body's immune system clears infections and also "remembers" them so that in the event of an encounter with the same or a similar virus, reinfection does not occur. But some viruses – such as CMV – outsmart the immune system. The OHSU team demonstrated that rhesus CMV can reinfect rhesus macaques (RM) that are highly immune against CMV because they already harbor a persistent infection by the same virus. This remarkable feat is possible because the incoming virus encodes proteins that inhibit major histocompatibility complex class I (MHC-I) antigen presentation, a process that normally alerts CD8+ "killer" T cells to an ongoing infection.
"We showed that CMV evades the immune alert systems by making genes that disrupt the MHC-I molecules' ability to communicate an ongoing infection to the T cells. InPickerandFruhphoto essence, CMV is able to cut off an infected cell's call for elimination. This allows CMV to overcome this critical immune barrier during reinfection," explained Dr. Früh.
When these MHC-I inhibitory genes were deleted from CMV, the virus was unable to reinfect unless the CD8+ T cells were transiently removed from the animals. MHC-I interference was also dispensable when CMV-negative RM were infected for the first time. These findings demonstrate that the viral MHC-I inhibitory genes (called US2-11 glycoproteins) promote evasion of CD8+ T cells in vivo, thus explaining why CMV can so easily overcome pre-existing immune responses.
CMV infects up to 80 percent of the U.S. population before age 40, reinfecting people again and again even though their immune systems strongly respond to it. For most people, CMV infection goes undetected and they do not become seriously ill. However, in vulnerable populations with weaker immune systems, such as infants, organ donor recipients and human immunodeficiency virus (HIV) patients, CMV poses a potentially deadly risk.
This research suggests that it will be challenging to develop a vaccine to prevent CMV infection, although it might still be possible to limit CMV-associated symptoms and disease by vaccination. However, this research also explains previous results by Dr. Picker who showed that CMV can be used repeatedly as a viral vector to induce immune responses against other pathogens, such as the immunodeficiency virus. Thanks to its unique immune evasion strategies, CMV-based vectors are not limited by vector-specific immunity unlike most other viral vectors that are currently in development.
This paper was reported on by several media outlets. You can read the Oregonian article here. Author listing: Scott G. Hansen, Colin J. Powers, Rebecca Richards, Abigail B. Ventura, Julia C. Ford, Don Siess, Michael K. Axthelm, Jay A. Nelson, Michael A. Jarvis, Louis J. Picker, Klaus Früh
A list of all OHSU-authored papers published in the past two months is here.
Pictured: Drs. Picker (left) and Früh.
ABOUT THE PAPER OF THE MONTH
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. A list of all papers compiled by the OHSU Library and published by OHSU faculty during the prior month is also provided here. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD, and reviewed by Dean Mark Richardson, MD, MBA, and Vice President/Senior Associate Dean for Research Dan Dorsa, PhD.