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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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