杏吧原创

Editorial: 鈥�We can win the AIDS war with drugs and vaccines鈥�

HIV doesn鈥檛 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 鈥� by fighting an infection without help from the immune system.

Using this approach, mice can keep HIV at bay even when given 100 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 鈥淧romising HIV-gel trial halted in Africa鈥�) this approach has yet to deliver significant success 鈥� perhaps in part because HIV targets and ultimately weakens cells of the immune system that we rely upon to mount a strong defence (see 鈥淗istory of vaccines鈥�).

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鈥檚 team has ignored it altogether. Their approach 鈥� part vaccine, part gene therapy 鈥� is to turn muscles into factories that churn out potent antibodies against HIV. Because muscle isn鈥檛 on HIV鈥檚 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.

鈥淲e produce a similar effect to a vaccine, but without ever calling on the immune system to do any of the work,鈥� says Alejandro Balazs, a member of Baltimore鈥檚 team also at Caltech.

鈥淲e produce a similar effect to a vaccine, but without ever calling on the immune system to do the work鈥�

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 鈥渋nfect鈥� the leg muscles of mice with genes that pump out the antibodies.

鈥淭he idea here is to basically supply the body with its own factory for making anti-HIV antibodies,鈥� says Baltimore.

The mice continued to make the antibodies throughout their lives, and stayed healthy despite the researchers鈥� best efforts to overwhelm them with HIV.

鈥淲e 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,鈥� says Balazs (Nature, ).

Because the mice in the experiment were equipped with human immune systems, Baltimore鈥檚 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 鈥� but they won鈥檛 know for sure until they begin clinical trials.

Baltimore says such a trial could start in one to two years. 鈥淎s soon as we manufacture clinical grade materials, get regulatory approval and organise a trial, we hope to get going,鈥� he says.

Another team led by at the Children鈥檚 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 SIV, the monkey equivalent of HIV (New 杏吧原创, 22 May 2009, p 12).

鈥淲e鈥檙e gratified to hear that our work in the macaques has been confirmed in a humanised mouse model using HIV,鈥� says Johnson. 鈥淲e鈥檙e moving ahead with our plans to test the concept in human trials.鈥� For the trial, Johnson鈥檚 team will also be using AAV injected into muscle, loaded with the gene for making a potent antibody.

Baltimore鈥檚 trial has confirmed something else: that the potent antibodies produced by the mouse muscles in the new trial are exceptionally formidable against HIV. Called 鈥渂roadly neutralising antibodies鈥�, they were first isolated from people with HIV in 2009. Lab tests show they are typically active against at least of 90 per cent of all known strains of HIV.

鈥淭he results of this study are further evidence that broadly neutralising antibodies could confer high-level protection against HIV infection,鈥� says , chief scientific officer at the . Koff says that we now know of 20 broadly neutralising antibodies, with .

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. 鈥淭here鈥檚 no reason why we couldn鈥檛 make two or more antibodies by using multiple AAVs simultaneously.鈥�

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 鈥渙ff the peg鈥� has great potential.

鈥淗owever, the key issues are whether the vaccine will work as well in people, and whether it will be safe to use,鈥� 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. 鈥淭his latest approach should certainly be studied further, but doesn鈥檛 negate the need to continue research for an HIV vaccine,鈥� he says. 鈥淎ll approaches should be supported in efforts to prevent and control HIV, which still infected an estimated 2.7 million people last year alone.鈥�

Cate Hankins, chief scientific adviser at , 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.