[Nikolas]

Study shows that inhibiting interferons may help clear the body of persistent viral infection.

Persistent viral infections have long baffled virologists, who were unable to explain how some viruses manage to avoid the bodies critical immune response and remain ‘hidden’. A new study, published April 12th in Science Magazine, may shed some new light on this phenomenon.

Scientists at The Scripps Research Institute have made a new discovery that led to counterintuitive conclusions that gives potential to clear persistent infection that is the hallmark of such diseases as AIDS, hepatitis B and hepatitis C.

The study focused on the activity of the body's type 1 interferon proteins. Since its discovery over 50 years ago, IFN-I has been believed to be an especially powerful antiviral agent that marshals the immune system's response against the body's foreign invaders. But in the new study, scientists document that IFN-I initiates persistent infection and limits the generation of an effective antiviral immune response in mice.

"Our findings illuminate an unexpected role for IFN-I proteins in persistent infections, which has major implications for how we treat these infections," said Michael B. A. Oldstone, a professor in the Department of Immunology and Microbial Science at TSRI and senior investigator for the study.

For decades, virologists around the world have been trying to figure out how some viruses manage to persist in their hosts and avoid detection by the immune system.

A discovery made in recent years shows that some of these viruses are specialized at getting into cells of the immune system known as dendritic cells. These cells serve as key detectors in cases of infection and normally respond to viral infections by producing IFN-I proteins. They also produce cytokines and chemokines, both immune-enhancing proteins that drive forward immune responses, as well as immune-suppressing proteins including interleukin-10 (IL-10) and PD-1, which act as a warning system that balances the immune response to keep it within healthy limits, and prevent auto-immune responses.

It has been shown that persistent viruses can turn this immune-suppressing effect and use it for their own purposes. In several experimental models of persistent infections in humans, a rise in IL-10 and PD-L1 is rapidly followed by declines in the function and numbers of antiviral T-cells. Many of the surviving T cells are rendered ineffective, an occurrence called "T-cell exhaustion" or "hyporesponsiveness."

To figure out this immune-suppressing response, Oldstone and his team looked at the early events in a persistent viral infection. The team used a standard animal model that Oldstone himself developed almost 30 years ago: laboratory mice infected with lymphocytic choriomeningitis virus (LCMV) Clone (Cl) 13 strain.

One initial observation was surprising. "A day after infection, bloodstream levels of IFN-I were at least several times higher in the persistent infection, compared to a non-persistent LCMV infection," said Teijaro, one of the lead authors of the study.

The persistent LCMV Cl 13 strain also showed to be much better at infecting plasmacytoid dendritic cells which are considered the main source of IFN-I proteins during viral infections. This specific strain is Differs from others only in three amino-acids, of which just two are important; one in the glycoprotein for binding and entry into dendritic cells and the other in the viral polymerase that enhances viral replication.
Up until now, production of IFN-Is by plasmacytoid dendritic cells has been considered a normal and beneficial part of the immune reaction to a viral infection. "We usually think of IFN-I proteins as antiviral proteins, so that more IFN is better," said Ng, another of the lead researchers on this project. Once she and Teijaro used a monoclonal antibody to block IFN-I-alpha-beta receptor, activity just before or after infection with Cl 13, they noticed a sharp drop in the production of IL-10 and PD-L1, a reduction in cytokine and chemokine expression levels and maintenance of normal secondary lymphoid tissue structure.

Over a longer time period, as the scientists found, levels of immune-suppressing IL-10, as well as PD-L1, both inducers of T-cell exhaustion noticeably drop, and that was associated with restoration of antiviral immune response and virus clearance. Even though blocking the IFN-I-a-b receptor led to higher bloodstream levels of the viruses in the first days of the infection, it soon brought about a stronger, infection-clearing response.

"Even when we blocked IFN-I-a-b receptor after a persistent infection had been established and T-cell exhaustion had set in, we still saw a significantly earlier clearance of the virus," Ng said.

The team now plans to study IFN-I signaling pathways in greater detail. In particular, they hope to determine whether the IFN-I-a-b receptor blocking strategy can work against chronic viral infections in humans. They will also be seeking small molecules which can mimic the function of receptor blocking.

"Most of our findings in the LCMV model mirror what has been observed in human persistent infections, namely the up regulation of IL-10 and PD-L1, and the disruption of lymphoid architecture," said Oldstone.


"Persistent LCMV infection is controlled by blockade of type 1 interferon signaling” Kathleen C. F. Sheehan and Robert D. Schreiber of Washington School of Medicine at St. Louis; and Megan J. Welch, Andrew M. Lee, and Juan Carlos de la Torre of TSRI.
The study was supported by the National Institutes of Health grants AI009484, AI057160 and AI077719, as well as an American Heart Association Fellowship (11POST7430106).