Scripps Institute. US: In a remarkable new advance against the virus that causes AIDS,
scientists from the Jupiter, Florida campus of The Scripps Research
Institute (TSRI) have announced the creation of a novel drug candidate
that is so potent and universally effective, it might work as part of an
unconventional vaccine.
The research, which involved scientists from more than a dozen
research institutions, was published February 18 online ahead of print
by the prestigious journal Nature.
The study shows that the new drug candidate blocks every strain of
HIV-1, HIV-2 and SIV (simian immunodeficiency virus) that has been
isolated from humans or rhesus macaques, including the hardest-to-stop
variants. It also protects against much-higher doses of virus than occur
in most human transmission and does so for at least eight months after
injection.
“Our compound is the broadest and most potent entry inhibitor
described so far,” said Michael Farzan, a TSRI professor who led the
effort. “Unlike antibodies, which fail to neutralize a large fraction of
HIV-1 strains, our protein has been effective against all strains
tested, raising the possibility it could offer an effective HIV vaccine
alternative.”
Blocking a Second Site
When HIV infects a cell, it targets the CD4 lymphocyte, an integral
part of the body’s immune system. HIV fuses with the cell and inserts
its own genetic material—in this case, single-stranded RNA—and
transforms the host cell into a HIV manufacturing site.
The new study builds on previous discoveries by the Farzan
laboratory, which show that a co-receptor called CCR5 contains unusual
modifications in its critical HIV-binding region, and that proteins
based on this region can be used to prevent infection.
With this knowledge, Farzan and his team developed the new drug
candidate so that it binds to two sites on the surface of the virus
simultaneously, preventing entry of HIV into the host cell. “When
antibodies try to mimic the receptor, they touch a lot of other parts of
the viral envelope that HIV can change with ease,” said TSRI Research
Associate Matthew Gardner, the first author of the study with Lisa M.
Kattenhorn of Harvard Medical School. “We’ve developed a direct mimic of
the receptors without providing many avenues that the virus can use to
escape, so we catch every virus thus far.”
The team also leveraged preexisting technology in designing a
delivery vehicle—an engineered adeno-associated virus, a small,
relatively innocuous virus that causes no disease. Once injected into
muscle tissue, like HIV itself, the vehicle turns those cells into
“factories” that could produce enough of the new protective protein to
last for years, perhaps decades, Farzan said.
Data from the new study showed the drug candidate binds to the
envelope of HIV-1 more potently than the best broadly neutralizing
antibodies against the virus. Also, when macaque models were inoculated
with the drug candidate, they were protected from multiple challenges by
SIV.
“This is the culmination of more than a decade’s worth of work on the
biochemistry of how HIV enters cells,” Farzan said. “When we did our
original work on CCR5, people thought it was interesting, but no one saw
the therapeutic potential. That potential is starting to be realized.”
In addition to Farzan, Gardner and Kattenhorn, authors of the study,
“AAV-expressed eCD4-Ig provides durable protection from multiple SHIV
challenges,” include Hema R. Kondur, Tatyana Dorfman, Charles C. Bailey,
Christoph H. Fellinger, Vinita R. Josh, Brian D. Quinlan, Pascal
Poignard and Dennis R. Burton of TSRI; Jessica J. Chiang, Michael D.
Alpert, Annie Y. Yao and Ronald C. Desrosiers of Harvard Medical School;
Kevin G. Haworth and Paula M. Cannon of the University of Southern
California; Julie M. Decker and Beatrice H. Hahn of the University of
Pennsylvania; Sebastian P. Fuchs and Jose M. Martinez-Navio of the
University of Miami Miller School of Medicine; Hugo Mouquet and Michel
C. Nussenzweig of The Rockefeller University; Jason Gorman, Baoshan
Zhang and Peter D. Kwong of the National Institutes of Health; Michael
Piatak Jr. and Jeffrey D. Lifson of the Frederick National Laboratory
for Cancer Research; Guangping Gao of the University of Massachusetts
Medical School; David T. Evans of the University of Wisconsin; and
Michael S. Seaman of Beth Israel Deaconess Medical Center.
The work was supported by the National Institutes of Health (grants
R01 AI091476, R01 AI080324, P01 AI100263, RR000168 and R01AI058715).