Over the past year, researchers at the California
Institute of Technology (Caltech), and around the world, have been studying a
group of potent antibodies that have the ability to neutralize HIV in the laboratory;
their hope is that they may learn how to create a vaccine that makes antibodies
with similar properties. Now, biologists at Caltech led by Nobel Laureate David
Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology,
have taken one step closer to that goal: They have developed a way to deliver
these antibodies to mice and, in so doing, have effectively protected them from
HIV infection.
This new approach to HIV prevention—called Vectored
ImmunoProphylaxis, or VIP—is outlined in Nature.
Traditional efforts to develop a vaccine against HIV have
been centered on designing substances that provoke an effective immune
response—either in the form of antibodies to block infection or T-cells that
attack infected cells. With VIP, protective antibodies are being provided up
front.
“VIP has a similar effect to a vaccine, but without
ever calling on the immune system to do any of the work,” says Alejandro
Balazs, lead author of the study and a postdoctoral scholar in Baltimore’s lab. “Normally, you put an
antigen or killed bacteria or something into the body,
and the immune system figures out how to make an antibody against it. We’ve
taken that whole part out of the equation.”
Because mice are not sensitive to HIV, the researchers
used specialized mice carrying human immune cells that are able to grow HIV.
They utilized an adeno-associated virus (AAV)—a small, harmless virus that has
been useful in gene-therapy trials—as a carrier to deliver genes that are able
to specify antibody production. The AAV was injected into the leg muscle of
mice, and the muscle cells then put broadly neutralizing antibodies into the
animals’ circulatory systems. After just a single AAV injection, the mice
produced high concentrations of these antibodies for the rest of their lives,
as shown by intermittent sampling of their blood. Remarkably, these antibodies
protected the mice from infection when the researchers exposed them to HIV
intravenously.
The team points out that the leap from mice to humans is
large—the fact that the approach works in mice does not necessarily mean it
will be successful in humans. Still, the researchers believe that the large
amounts of antibodies that the mice were able to produce—coupled with the
finding that a relatively small amount of antibody has proved protective in the
mice—may translate into human protection against HIV infection.
“We’re not promising that we’ve actually solved the
human problem,” says Baltimore.
“But the evidence for prevention in these mice is very clear.”
The paper also notes that in the mouse model, VIP worked
even in the face of increased exposure to HIV. To test the efficacy of the
antibody, the researchers started with a virus dose of one nanogram, which was
enough to infect the majority of the mice who received it. When they saw that
the mice given VIP could withstand that dose, they continued to bump it up
until they were challenging them with 125 nanograms of virus.
“We expected that at some dose, the antibodies would
fail to protect the mice, but it never did—even when we gave mice 100 times
more HIV than would be needed to infect seven out of eight mice,” says
Balazs. “All of the exposures in this work were significantly larger than
a human being would be likely to encounter.”
He points out that this outcome likely had more to do
with the properties of the antibody that was tested than the method, but adds
that VIP is what enabled the large amount of this powerful antibody to
circulate through the mice and fight the virus. Furthermore, VIP is a platform
technique, meaning that as more potent neutralizing antibodies are isolated or
developed for HIV or other infectious organisms, they can also be delivered
using this method.
“If humans are like mice, then we have devised a way
to protect against the transmission of HIV from person to person,” says Baltimore. “But that
is a huge if, and so the next step is to try to find out
whether humans behave like mice.”
He says the team is currently in the process of
developing a plan to test their method in human clinical trials. The initial
tests will ask whether the AAV vector can program the muscle of humans to make
levels of antibody that would be expected to be protective against HIV.
“In typical vaccine studies,
those inoculated usually mount an immune response—you just don’t know if it’s
going to work to fight the virus,” explains Balazs. “In this case,
because we already know that the antibodies work, my opinion is that if we can
induce production of sufficient antibody in people, then the odds that VIP will
be successful are actually pretty high.”
Filed Under: Drug Discovery
