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New therapeutic target for cold, flu viruses identified

Aug. 9, 2012, 10:49 AM

John Williams, M.D., left, and colleagues, from left, John Erickson, Andrew Hastings and Sharon Tollefson are studying how viruses that cause acute respiratory infections disable immune cells. (photo by Joe Howell)

Viruses that cause acute respiratory infections — such as human metapneumovirus (HMPV) and flu — impair a set of immune system cells that should clear the virus from the lungs.
Now, Vanderbilt University investigators have discovered the signaling pathway that disables these immune cells.

The findings, reported in the Aug. 1 Journal of Clinical Investigation, suggest that this signaling pathway may be a good target for treating acute respiratory viral infections and may lead to better vaccines.

“We stumbled onto the solution for this decade-old mystery of how respiratory viruses induce wimpy T cells (a type of immune cells),” which might explain how these viruses cause recurrent infections throughout life, said John Williams, M.D., associate professor of Pediatrics and of Pathology, Microbiology and Immunology.

Graduate student John Erickson was exploring the immune response in mice infected with HMPV, a leading cause of serious respiratory illness in young children and the elderly.

He found high levels of HMPV-targeted CD8 T cells, but the cells were not producing cytokines (factors to aid in fighting infection) or killing virus-infected cells.

“The T cells weren’t functional, and they actually became more impaired as time went on, even after the acute infection was gone,” said Williams.

Other studies had reported non-functional T cells following respiratory syncytial virus (RSV), influenza and parainfluenza virus infection, but it was not clear how the T cells were becoming impaired.

A similar “T cell exhaustion” also had been observed in chronic HIV and hepatitis C infections and in cancer, and investigators had linked this phenomenon to a signaling pathway initiated by the protein PD-1.

“PD-1 is a marker of an impaired or exhausted T cell,” Williams said. PD-1, he added, likely functions normally to “put a little bit of a brake on the T cells” and keep inflammation in check. In chronic infections and cancer though, it puts the brakes on too hard. Blocking PD-1 (in clinical trials in patients with cancer) is proving to be effective in re-activating exhausted T cells, which then kill the tumor.

“It’s a very exciting direction for cancer and chronic infections — the idea of blocking PD-1 signaling to ‘wake up’ these T cells, but this pathway hadn’t been considered or studied much in acute infections,” Williams said.

Williams and his team wondered if PD-1 also might be responsible for the impaired T cells following HMPV infection in mice. They found high levels of PD-1 after HMPV infection and also after influenza and vaccinia virus infections.

“Essentially any respiratory viral infection — even though they’re acute infections, they induce exhausted CD8 T cells that express this PD-1 marker,” Williams said.

Using a PD-1 blocking drug, the researchers were able to restore function to the T cells, which then cleared virus faster. Mice missing the PD-1 gene also had more functional T cells and cleared virus more quickly.

In lung biopsy samples from patients who died with RSV, influenza or parainfluenza virus infections, the researchers also found high levels of PD-1, suggesting that the same signaling pathway is active in humans.

Williams is excited that his team solved the mystery of impaired T cells after acute viral infections, and he’s hopeful about the potential for treating HMPV, RSV and parainfluenza infections, for which there are no anti-viral medications.

“Drugs that block PD-1 signaling (currently in trials for chronic infections and cancer) might have utility in acute respiratory infections, to boost the T cells a bit, take the brakes off and allow them to clear the infection,” Williams said.

The researchers are also intrigued by the possibility that blocking PD-1 signaling during vaccination may allow humans to mount a better immune response and build an effective immune memory against these respiratory viruses. They have ongoing studies in mice to explore this possibility.

“We think there’s a window there, that we can block PD-1 signaling to boost the T cells somewhat to get rid of infection or to create better immune memory, without causing autoimmune problems. That’s our hope, anyway.”

Other authors include Pavlo Gilchuk, Ph.D., Andrew Hastings, Sharon Tollefson, Monika Johnson, Melissa Downing, Kelli Boyd, Ph.D., Joyce Johnson, M.D., Annette Kim, M.D., Ph.D., and Sebastian Joyce, Ph.D. The research was supported by grants from the National Institutes of Health (AI085062, AI082417, AI040079, AI042286, HL054977, GM007347), and in part by the Vanderbilt CTSA grant (RR024975).

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