As a gene therapy vehicle, adenovirus is most famous for its role in the death of teenager Jesse Gelsinger in 1999, marking the first death in a gene therapy clinical trial.

But despite that tragedy, the virus has many advantages for gene transfer and so still is used extensively, and correspondingly extensively studied, in gene therapy research. In the Feb. 8, 2008, issue of Cell, researchers reported new findings on how the virus enters cells that may lead to new ways to target it to specific cell populations.

One of the drawbacks of adenovirus is that it has its own ideas about where it wants to go. Specifically, when the virus is delivered via the bloodstream, it tends to accumulate in the liver.

The adenoviral fondness for the liver can be a plus or a minus - some gene therapies aimed at correcting metabolic deficiencies target the liver.

That was the case in the trial that Gelsinger participated in. In that trial, researchers were trying to deliver the enzyme ornithine transcarbamylase to the liver to correct an inability to clear ammonia from the bloodstream. (Gelsinger died of an out-of-control inflammatory response to the virus that ultimately caused organ failure.)

But in other cases, it is vital to keep the virus away from the liver - Cell paper senior author Andy Baker mentioned cancer gene therapy as an example, where the goal is to deliver toxic genes to tumor cells. Researchers have had success injecting adenoviral vector directly into tumors, but when it is in the bloodstream, it accumulates in the liver.

And in the most basic sense, Baker told BioWorld Today, "you need to understand how and why the virus goes to the liver" no matter what the therapeutic goal of manipulating it is.

In their Cell paper, Baker, who is professor of molecular medicine at the University of Glasgow in Scotland, and his colleagues have done just that. They showed that of the three major viral coat proteins, it is the so-called hexon protein that is critical for getting the virus into liver cells when the virus is delivered through the bloodstream.

Much of the attention has focused on another coat protein, named fiber, because it bound to proteins in the blood, and the resulting complex was able to bind other receptors on liver cells.

One strategy has been to mutate the fiber protein. Unfortunately, though, it hasn't been successful, at least not consistently so. Baker said that "there is a huge amount of literature" on fiber, with seemingly identical experiments coming to opposite conclusions at times.

Another recent study, however, showed that mice with low levels of blood coagulation proteins had less virus accumulating in the liver, suggesting that host proteins do indeed play a role in helping the virus get into the liver.

The scientists determined the blood protein that was functioning as a mole was the factor X protein, one of the coagulation factors in the blood clotting cascade. In previous work, Baker and his colleagues had shown that mutating either fiber protein or the other major viral coat protein, penton, had no effects on the viral interaction with factor X or its entry into cells.

But in the experiments described in the current Cell, hexon binds to factor X, and that binding is necessary for gene transfer to occur. When the researchers mutated hexon, viral accumulation in liver cells was blocked. The authors also were able to block viral entry into liver cells by pharmacologically preventing hexon from binding to factor X.

Baker stressed that his findings do not mean that fiber protein is unimportant for adenoviral gene transfer. Virally mediated gene therapy, he said, is "a complex procedure of a series of steps," including viral docking, entry and expression of the corrective gene.

That's not to say that fiber is just there for decoration - Baker stressed that fiber protein is "undoubtedly very important" for other steps in the transduction cascade. But his team's results showed that when the virus is delivered via the blood, "hexon is the key molecule that gets the virus to the cell surface."