Hydrogen, HIV and Photographic Trickery

A modified virus encoding an anti-AIDS antibody can protect animals from HIV infection...

An estimated 7000 new cases of HIV occur each day, the majority of them in developing countries where access to heathcare and antiretroviral drugs is limited. For this reason, a vaccine is urgently needed to control the spread of the infection.

Previous vaccine strategies have performed poorly, barely making a dent in infection rates, and so far the only intervention with proven longterm efficacy has been circumcision, which reduces a man's risk of acquiring the disease by 60-80%.

But a paper published this week in Nature by Caltech scientist David Baltimore and his colleagues might hint at a new way to combat the problem. They've used a self-complementary adeno-associated virus 8 (scAAV-8) as a vector, to ferry into experimental animals the DNA code for an antibody called b-12, which has HIV-neutralising properties.

This antibody, discovered some years ago, is special because it has the capacity to disable many different strains of HIV and can prevent infection becoming established in the first place.

The Caltech team injected 100 billion particles of the scAAV-8 vector into the leg muscles of experimental mice. These animals had also been modified to carry in their bloodstreams the human CD4 white cells targeted by HIV.

Within a week, high levels of the human b-12 antibody were detectable in the blood of the mice and expression was sustained for at least one year, which was the duration of the experiment.

The researchers then challenged the animals with an injection of HIV sufficiently large to infect the vast majority of unvaccinated mice and tracked the numbers of CD4 cells circulating in the bloodstream.

Compared with control mice, in which the CD4 count dropped nearly to zero, the b-12 antibody-producing animals showed complete protection against the infection.

The result is stunning, but not without a few residual wrinkles that need ironing out. This is a study in mice and so the concept would need to be proven in humans. Also, the long-term tolerability and safety of sc-AAV vectors and the effect of sustained high-level expression of the b-12 antibody are unknown, and it's unclear how much of the viral vector would be required to protect larger species including humans.

However, according to the team, who dub their technique "VIP" - vectored immunoprophylaxis - "given the level of protection that VIP has demonstrated in vivo, we believe that highly effective prophylaxis through expression of existing monoclonal antibodies against HIV in humans is achievable."

A signal that controls the integrity of the blood brain barrier - the system that protects and chemically cocoons the brain from the rest of the body - has been discovered...

Early during embryonic development, the cells that line the blood vessels supplying the brain and spinal cord become tightly linked together, establishing a barrier that encloses the central nervous system and permits only certain things to pass through. Others, including immune cells, antibodies, chemicals and many pathogens are screened out.

But what controls the formation and operation of the blood brain barrier wasn't known. Now a team of scientists from Canada have cracked the problem and discovered the molecular key that locks and unlocks the barrier.

It all hinges, Alexandre Prat and his colleagues have shown, on a signal called sonic hedgehog. This is produced by brain cells called astrocytes, which are in contact with the endothelial cells in the blood vessels.

Writing in Science, the team show that, in the presence of sonic hedgehog, endothelial cells bind tightly together, immune cells and proteins are unable to escape from the cerebral circulation and the linings of the blood vessels express fewer cell adhesion molecules making it harder for inflammatory cells to cling on.

Applying a drug called cyclopamine, however, which blocks the action of sonic hedgehog, reversed all these effects. The drug also drammatically worsened the conditions of experimental animals with a multiple sclerosis (MS)-like disease caused by entry into the nervous system of white blood cells that attack the myelin sheath that surrounds nerve fibres. Reducing the integrity of the blood brain barrier appeared to enable more inflammatory cells to flock into the nervous system, amplifying the damage.

In line with this observation, brain samples tested from humans cases of MS show increased levels of sonic hedgehog production in areas where the disease was most active, suggesting that the brain upregulates the signal in an attempt to dampen inflammation.

Together, say the researchers, these data "provide compelling evidence suggesting a dual protective role for the hedgehog pathway at the level of the blood brain barrier and by acting as an endogenous anti-inflammatory system."

Moreover, these findings open up new therapeutic avenues that could be exploited to control entry of immune cells into the central nervous system and therefore reduce the rates of recurrence of MS attacks.