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Using Viruses to Find the Cellular Achilles Heel

Melanie Ott

SAN FRANCISCO, CA—January 22, 2015­—A study from researchers at the Gladstone Institutes has exposed new battle tactics employed by the hepatitis C virus (HCV). Published in the January 22 issue of Molecular Cell, the investigators created full protein interaction maps—interactomes—of where the virus comes into contact with the host proteins during the course of infection. Through these protein interactions, the scientists not only gained insight into the virus, they also uncovered a common set of host proteins that are targeted by various infections. Their results suggest that these proteins and the cellular processes they govern are the most crucial—in effect, the collective Achilles heel—for both the human body and its viral invaders.

“Viruses are fantastic tools for shedding new light on human biology,” says Nevan Krogan, PhD, a senior investigator at the Gladstone Institutes and a corresponding author. “Viruses are relatively simple organisms—often they only have about 10-20 genes—but they wreak havoc on our system by targeting key proteins and essential functional pathways in every major biological process. This gives us great insight into what the critical mechanisms are that are being hijacked during infection, and it helps us to develop new strategies for preventing or stemming disease.”

Dr. Krogan, who is also a professor of cellular and molecular pharmacology at the University of California, San Francisco (UCSF) and director of the UCSF branch of QB3, partnered with Gladstone senior investigator Melanie Ott, MD, PhD, to map the interaction between the proteins in HCV and those in the human liver cells that HCV infects. This resulted in over 5,000 virus-host protein-to-protein interactions, which the investigators narrowed down to 139 key connections that are necessary for HCV infection, involving all 10 HCV proteins and 133 proteins in the host liver cells.

Although patients have benefited from numerous advancements in the treatment of HCV, how the virus damages the liver remains unknown. The HCV interactome map, led by first authors Holly Ramage, PhD, and G. Renuka Kumar, PhD, may help on this front.

“There’s a lot we still don’t know about HCV, like how it infects the cell, what processes it disrupts, and why it’s so harmful to the body,” explains Dr. Ott, who is also a professor of medicine at UCSF. “The protein interactome offers us an unbiased and global view of how the virus is affecting the infected cells, and this can help us to start answering a lot of the important questions. Ultimately, this information may direct us to new leads for preventative treatments for associated liver pathologies, like fibrosis and cancer.”

By removing the interacting host proteins from the cell one at a time, the researchers were able to determine what their functional contribution was in the infection process: whether the host proteins were hijacked by the virus and used to spread infection, or whether they were part of a defense mechanism against the virus. This revealed a new critical host mechanism that HCV inactivates and usurps to support its own survival and replication.

Publication: Ramage HR, Kumar GR, Verschueren E, Johnson JR, Dollen Von J, Johnson T, Newton B, Shah P, Horner J, Krogan NJ, Ott M (2015) A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol Cell 57:329–340.