Thursday, December 8, 2011

Fight HIV with Muscle Antibodies

HIV doesn't play by the rules: instead of dodging the immune system it attacks it head on. Now it seems our best hope for a vaccine against the killer virus might also involve tearing up the rule book — by fighting an infection without help from the immune system. Using this approach, mice can keep HIV at bay even when given loo times the virus that would be needed to cause a lethal infection. Conventional vaccines work by exposing the body to safe versions of a pathogen or parts of it, which primes the immune system to fight off future infection.
But like other failed attempts to tackle HIV (see page 4) this approach has yet to deliver significant success — perhaps in part because HIV targets and ultimately weakens cells of the immune system that we rely upon to mount a strong defence . David Baltimore of the California Institute of Technology in Pasadena, California, and colleagues are among a group of  researchers who have decided on a dramatic change of tack. Instead of trying to hone the immune system, Baltimore's team has ignored it altogether.
Their approach — part vaccine, part gene therapy — is to turn muscles into factories that churn out potent antibodies against HIV. Because muscle isn't on HIV's hitlist, it will continue to generate antibodies even after an HIV infection, making the strategy potentially better than one which tweaks the immune system to produce the antibodies. "We produce a similar effect to a vaccine, but without ever calling on the immune system to do any of the work," says Alejandro Balazs, a member of Baltimore's team also at Caltech.
The team loaded a harmless, cold-related virus called adeno-associated virus (AAV) with genes that make potent antibodies to HIV. Then they used them to "infect" the leg muscles of mice with genes that pump out the antibodies. "The idea here is to basically supply the body with its own factory for making anti-HIV antibodies," says Baltimore. The mice continued to make the antibodies throughout their lives, and stayed healthy despite the researchers best efforts to overwhelm them with HIV. "We expected that at some dose, the antibodies would fail to protect the mice, but there was no infection even when we gave mice 100 times more HIV than would be needed to infect seven out of eight mice," says Balazs (Nature, DOI: 10.1038/naturei0660).
Because the mice in the experiment were equipped with human immune systems, Baltimore's team could check that the therapy fought off HIV before the virus was able to weaken the conventional immune system. They suspect that people would react in the same way to the vaccine/gene therapy approach — but they won't know for sure until they begin clinical trials. Baltimore says such a trial could start in one to two years. "As soon as we manufacture clinical grade materials, get regulatory approval and organise a trial, we hope to get going," he says. Another team led by Philip Johnson at the Children's Hospital of Philadelphia, Pennsylvania, could beat them to it.
Johnson and his colleagues used almost exactly the same strategy two years ago to protect macaques against Sly, the monkey equivalent of HIV (New Scientist, 22 May 2009, p 12). "We're gratified to hear that our work in the macaques has been confirmed in a humanised mouse model using HIV," says Johnson. "We're moving ahead with our plans to test the concept in human trials." For the trial, Johnson's team will also be using AAV injected into muscle, loaded with the gene for making a potent antibody.
Baltimore's trial has confirmed something else. that the potent antibodies produced by the mouse muscles in the new trial are exceptionally formidable against HIV. Called "broadly neutralising antibodies", they were first isolated from people with HIV in 2009. Lab tests show they are typically active against at least of go per cent of all known strains of HIV. "The results of this study are further evidence that broadly neutralising antibodies could confer high-level protection against HIV infection," says Wayne Koff, chief scientific officer at the International AIDS Vaccine Initiative. Koff says that we now know of 20 broadly neutralising antibodies, with 17 new ones reported only this August.
 Although the AAVs injected into the mice each carried genes to make only one antibody, people could be given broader protection by injecting their muscles with several AAVs that each make a different antibody, Baltimore says. "There's no reason why we couldn't make two or more antibodies by using multiple AAVs simultaneously." Lucy Dorrell of the Weatherall Institute of Molecular Medicine in Oxford, UK, says that one of the major obstacles conventional HIV vaccines face is priming the body to make broadly neutralising antibodies, so a method that delivers them "off the peg" has great potential. "However, the key issues are whether the vaccine will work as well in people, and whether it will be safe to use," she says.
 Koff stresses that, encouraging though the new results are, they should not be used as an excuse to abandon the quest for a conventional vaccine that primes the immune system. "This latest approach should certainly be studied further, but doesn't negate the need to continue research for an HIV vaccine," he says. "All approaches should be supported in efforts to prevent  and control HIV, which still infected an estimated 2.7 million people last year alone." Cate Hankins, chief scientific adviser at UNAIDS, agrees, pointing out that in September at the AIDS Vaccine 2011 conference in Bangkok, Thailand, models based on sexual behaviour showed that RV 144, the best performing conventional vaccine so far, could still prevent thousands of infections, even though it reduces the overall risk by just 31 per cent.



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