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There are some major differences, of course, between FIV and HIV. Perhaps the biggest difference is that HIV cannot infect cats and FIV cannot infect humans—in fact, there is zero evidence that FIV has ever infected humans at any time in the last 6,000 years, during which humans and cats have been living together.

For instance, there are differences in the accessory genes that the viruses use. FIV and HIV, like all lentiviruses, have a number of other "accessory" genes as well, with names like tat, rev, nef and vif. The roles of some of these genes are clear-cut—rev, for instance, helps the viral genome get into and out of the nucleus.

Others are more mysterious. "[Scientists are still trying to figure out what vif does," says elder, referring to the acronym for the "viral infectivity factor" gene. "But both FIV and HIV need it."

At this level, the differences between the two viruses are more apparent. HIV has an accessory gene called nef, while FIV does not. And FIV has a different accessory gene called a dUTPase that HIV does not have. "This gene helps the virus get around in non-dividing cells," says Elder.

The differences can be explained by the fact that the two different viruses have had to adapt to different hosts. Each virus must get along in its own particular host, and given its high replication and mutation rate has had the opportunity to pick up genes that presumably help it make more virus.

HIV and FIV live in completely different host organisms, which offer different challenges to the viruses in terms of how they can replicate and survive in each species' lifecycle. For instance, the primary mode of transmission of FIV is through animal bites, whereas that of HIV is through heterosexual intercourse.

But for a scientist like Elder, what is really interesting is how these molecules might be targets for therapy.

Molecular Targets

Elder, his laboratory, and his collaborators at TSRI and other institutions are trying to make more broad-based inhibitors of the two viruses.

"We're trying to make drugs that are efficacious for HIV and FIV," says Elder. "The idea is that if we can make broad-based inhibitors that hit FIV, maybe they will hit more HIV subtypes as well."

They look, for instance, at the FIV integrase as a target for therapeutics. This enzyme, as its name implies, is responsible for integrating the viral genome into the DNA of the host cell. They also look at the FIV protease, the protein that processes the virus's long polyprotein strips into the pieces necessary to package FIV into new infectious virus particles.

Like the viruses themselves, the HIV and FIV proteases are very similar. They have a 32 percent amino acid identity and essentially the same three-dimensional structure.

"If I showed you two pictures of FIV protease and HIV protease, you couldn't tell them apart," says Elder. Yet, strangely, the two proteases respond differently to the same inhibitors. Common drugs that inhibit HIV protease and are used for treating AIDS do not work on the FIV protease at all.

This observation led Elder, in collaboration with TSRI investigators Chi-Huey Wong, Bruce Torbett, Arthur Olson, and several others, to examine the structures of FIV protease and HIV protease to see what subtle differences between them could cause such a great distinction. It was research associate Taekyu Lee in Wong's group who noticed a region of the FIV protease that was smaller than the corresponding region in HIV protease. This prompted Wong to replace the inhibitor residue that fits in that site with a smaller amino acid. When they did this, the potency of this inhibitor increased 1,000-fold for FIV.

"This was the best [inhibitor] we had ever seen against FIV," says Elder, adding that it was also efficacious against the wild-type HIV and nine out of thirteen protease-resistant HIV isolates tested. In other words, the molecular changes that allowed many variants of HIV to escape drug therapies were the same as those that made FIV distinct from HIV.

Another protein that he is looking at is the virus-surface glycoproteins encoded by the env gene. He is particularly interested in elucidating the rules that determine which cells a virus coated with a particular glycoprotein can enter.

Some FIV virions are able to infect one type of cell and not another, while others infect the other cells and not the first. What determines these specificities are the structure of the particular glycoproteins—some of them bind to CXCR4 directly, whereas others need the interaction of a co-receptor to aid in the binding. Elder and his colleagues are trying to work out how and why this is so.

There's No Place Like Hope

Finally, Elder and his laboratory also look at the development of vaccines in HIV and FIV.

In this arena, there was a highly publicized report a few months ago on the failure of one vaccine against HIV to prove efficacious in a large Phase-III clinical trial. A few months before this, however, one big success was reported by a small manufacturer of animal medicines in a quiet suburb of Kansas City. This company, Fort Dodge Animal Health, a division of Wyeth, reported in September that the U.S. Department of Agriculture provided license for manufacture of the first prophylactic vaccine against FIV. In its press release, the company reports that the vaccine, called "Fel-O-Vax® FIV," has an 84 percent efficacy rate.

While this is certainly good news for cats and cat lovers, it is also good news for those concerned about HIV, because it means that despite the recent failure of one HIV vaccine, it is possible to design a vaccine against a lentivirus similar to HIV.


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Sequencing the genetic codes of various HIV and FIV isolates allows Elder and his laboratory to identify mutations that are involved in drug resistance. Photo by Jason S. Bardi.