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Nearly 30 years after the discovery of the virus that causes AIDS, contracting the
disease is no longer a quick death sentence. While high-tech therapies help patients
live longer, healthier lives, one University of Missouri researcher is fighting
HIV on another level — with a microbicide that stops the virus in its tracks.
Stefan Sarafianos, PhD, assistant professor of microbiology and immunology in the MU School of Medicine, and his collaborators Michael Parniak, PhD, at the University of Pittsburgh and Hiroaki Mitsuya, MD, PHD, at the National Institutes of Health have shown that the molecule EFdA can be used as a highly effective microbicide to prevent HIV transmission. They are in the process of patenting the chemical compound, which is up to 60,000 times more powerful than any other drug currently used for the treatment of HIV infection.
EFdA is a nucleoside reverse transcriptase inhibitor, meaning it targets the main
HIV enzyme responsible for viral replication. In laboratory tests, human cells treated
with EFdA can still become infected with HIV, but the compound stops the virus from
replicating and spreading. Then, the immune system rids cells of the invader.
“The immune system has the capability to kill a little of the virus in the background,
so it becomes manageable,” Sarafianos said. “Infection is the result of an overwhelming
attack of the virus, but if you manage to keep the viral load low, the body has
mechanisms to defend itself and clean up the virus on its own.”
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Structure of HIV
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With HIV vaccine efforts at an impasse, increased emphasis is placed on the discovery
of alternate strategies to prevent HIV infection. Internationally, researchers are
focused on developing microbicides that contain the same or related antiretroviral
drugs used as treatments for people infected with HIV. Scientists hope the drugs
can double as preventive agents in the form of vaginal gels and creams, empowering
women to protect themselves when their partners refuse to use condoms.
One of the most popular drugs, tenofovir, is being tested as a microbicide in gel
form. When EFdA is tested head-to-head with tenofovir in lab trials, there’s no
competition, Sarafianos said.
“EFdA provides a much longer-term barrier to HIV infection, up to days whereas other
microbicides last hours,” Sarafianos said. “EFdA also has a low toxicity against
normal cells, and it is active against a broad spectrum of HIV subtypes.”
Sarafianos co-investigator Michael Parniak, a professor of microbiology and molecular genetics, has spent more than 15 years studying and developing antiviral drugs for HIV/AIDS. His work in this area has resulted in eight patents issued or pending. Along with EFdA, he is developing the antiviral drug UC781, which is currently in clinical trials as a microbicide to prevent HIV transmission.
Parniak calls EFdA the most potent HIV inhibitor discovered so far.
“To me, this is the molecule that should and will move forward as a microbicide,”
Parniak said. “A combination of EFdA and UC781 would be a powerhouse, a one-two
punch pretty much guaranteeing significant blockage of HIV transmission.”
Just as an EFdA and UC781 combination could someday knockout HIV, Sarafianos and
Parniak posses a dynamic and complementary working relationship. Parniak, who specializes
in virology, is the principal investigator for the microbicidal use of EFdA, while
Sarafianos is the biochemical expert and principal investigator for work to understand
EFdA’s mechanism of action — he understands precisely how EFdA works against the
virus.
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Sarafianos
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Sarafianos, Parniak and Hiroaki Mitsuya, head of the experimental retrovirology section at the NIH and inventor of several approved HIV drugs, recently submitted a patent disclosure. The scientists now have one year to apply for a patent to use EFdA, originally synthesized by the Japanese company Yamasa, to minimize the sexual transmission of HIV. Once patented, the microbicide could be integrated into a product already commonly used for protection during sexual intercourse, such as a spermicide or other form of birth control.
“If we can reduce the transmission of HIV, we can finally get a handle on overall
infection spread,” Parniak said. “If we could reduce HIV transmission by only 30
percent or 40 percent, that would make a huge difference.”
According to estimates by the World Health Organization and UNAIDS, 33 million people
were living with HIV at the end of 2007. That same year, some 2.7 million people
became newly infected, and 2 million died of AIDS, including 270 000 children.
In the distant future, EFdA could also evolve into a treatment for patients already
infected with HIV. In a study conducted by Parniak at the University of Pittsburgh,
EFdA effectively treated rhesus monkeys infected with simian immunodeficiency virus
(SIV) who showed end-stage simian AIDS symptoms. Monkeys with end-stage SAIDS typically
die within a few weeks; the EFdA-treated animals lived for more than six months, a positive predictor that EFdA could have a similar effect in
humans.
Parniak attributes much of EFdA’s potential to the novel mechanism of action discovered
by Sarafianos’ lab at MU.
“He’s so excited about research, that he recharges me every time,” Parniak said
of their weekly conversations to share data. “He’s one of our brightest young investigators
and a real gem for Mizzou.”
The investigators’ EFdA research is funded by seven grants. Funding sources include
multiple NIH grants, a grant from the American Foundation for AIDS Research and
indirect federal funding of Sarafianos’ lab in MU’s Christopher S. Bond Life Sciences
Center.
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