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Using a virus against itself

By Lauren Arcuri

With most pathogens, says David Leib, Ph.D., a professor of microbiology and immunology, "you either get better, or you die."

But that paradigm doesn't hold with the herpes simplex virus (HSV), which takes up residence in the host and usually remains for the host's lifetime, a paradox that piqued Leib's interest years ago. "How is it possible that a virus can outlive the host?" he wanted to know.

A study by Leib and postdoctoral researcher Philipe Gobeil, Ph.D., sheds some light on that question, but the results were so surprising that at first Leib didn't believe them. "I told [Gobeil] he must have mislabeled his tubes or switched his samples," Leib says. So Gobeil repeated the work, and then repeated it again, eventually convincing Leib. They found that one of the virus's genes helps it defeat the human immune system "in a very specific, very clever way," as Leib puts it.

One of the virus's genes helps it defeat the human immune system "in a very specific, very clever way."

Leib has long studied an HSV protein called gamma-34.5. Early on, he discovered that this protein allows the virus to evade the host's interferon response, a nonspecific activation of the immune system that is important in eliminating viruses. Leib kept investigating and eventually found that there was more to the protein's action. "It also helps evade the more specific responses that our T cells make, the responses that are critical for us to remain permanently immune to an infection," Leib says.

Leib and Gobeil discovered that gamma-34.5 prevents autophagy of HSV by dendritic cells. Autophagy translates literally as "self-eating," and it is what cells do in response to starvation. They digest proteins within the cell, breaking them down into their constituent amino acids. It's a fundamental process that occurs in organisms as simple as yeast and as complex as humans. The immune system also uses autophagy to break down invaders, such as viruses.

One way that dendritic cells stimulate immunity is by digesting a protein from the virus via autophagy and then presenting it as an antigen on the cell surface. This allows the immune system's specific responders, the T cells, to make antibodies geared to the viral antigen. By shutting this process off, gamma-34.5 helps HSV survive indefinitely in the cell.

Leib engineered a herpes virus that lacks the gamma-34.5 protein and found that infected cells were more effective at presenting this version to T cells. The T cells, in turn, responded more robustly to the virus. One implication is the possibility that an HSV lacking the gamma-34.5 gene could be used as a vaccine against the virus, since it both weakens the virus and stimulates a stronger T-cell response. Leib says the next step is to see how well HSV can persist in the host without gamma-34.5, or if, in fact, it can be fully cleared from the system.

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Geisel School of Medicine at DartmouthDartmouth-Hitchcock Medical CenterWhite River Junction VAMCNorris Cotton Cancer CenterDartmouth College