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On Science: Continuing search for an AIDS vaccine

This article first appeared in the St. Louis Beacon, Sept. 9, 2009 - AIDS was much in the news last week, as researchers reported progress in the decades-long search for a vaccine. While this was certainly reason for good cheer, the news reports were muted at best. This is a road we have been down before, and often.

I wrote my first ON SCIENCE column on AIDS in July 1997, and have returned to the subject nine times in the following 10 years to report advances of one sort or another in the on-going battle to defeat HIV.

Every one of these advances was a real advance, in that we learned steadily more about the enemy we face - but there is still no vaccine after 10 years of trying by the best scientists in the world. Today about 33 million people live with HIV infections worldwide, and 2.7 million more will become infected this year. About 2 million will die of AIDS. So, is there any reason to be more hopeful now?

I think so. Note my muted tone. I feel today a little like the annual fall cartoon of Charlie Brown getting ready to run up and kick a football that Lucy has spotted on the ground for him. What is funny about the famous cartoon is that in past years Lucy has always pulled the ball away at the last moment, leaving Charlie Brown to fall ingloriously on his backside in the grass. Charlie never seems to learn. Every year he charges ahead anyway, full of hope that this time it will end differently. It never does.

So why am I playing Charlie Brown today, hopeful in the face of repeated failure? Partly because hope is the only option. And partly because I do see a ray of real scientific hope this time. To explain, I need to take you back a ways, to look at our failed quest for an AIDS vaccine. It is in exploring why we have failed that I see a more hopeful road forward.

Prodigious Mutations

The problem that has thwarted all efforts is that the HIV virus that causes AIDS has an unusually mistake-prone DNA copying enzyme. Making mistakes here and there as it produces offspring virus particles, HIV generates mutations ("typos" in genes) at a prodigious rate. That is why few of those infected with HIV have exactly the same virus.

Why is this a problem to vaccine researchers? To understand, you need to look for a moment at the way the antibody proteins induced by a vaccine defend you from virus infection. Antibodies don't attack viruses, but rather block their ability to enter cells. Each antibody tries to fit itself onto one of the virus proteins that almost always adhere to the surface of infected cells. Like matching two fingerprints, the match must be precise. When there is a perfect match, the antibody sounds a molecular alarm and the immune system makes a lot more of that antibody, inactivating all the HIV particles before they can enter any cells.

A vaccine works by exposing you to a protein of the disease-causing virus. Researchers use genetic engineering to insert an HIV gene into the DNA of an otherwise harmless virus. The engineered virus exposes you to that one HIV protein only -- the claw of a lion, not the whole dangerous HIV package -- so the immunization doesn't make you sick.

Your immune system responds to this call-to-arms by recruiting to your body's defense antibody-making cells, each able to make the antibody that recognized the HIV protein. Soon there are millions of these cells, each industriously churning out the virus-recognizing antibody.

Now you should be protected. If HIV infects you in the future, your blood is awash with antibody proteins waiting to pounce on any HIV attempting to infect cells and stop the AIDS infection before it gets started.

Only it doesn't.

Why not? The genes of HIV mutate so frequently that no two strains of HIV are alike. A vaccine targeted against one version is ineffective against others. Like a thief of many disguises, HIV is able to dodge any antibody a vaccine throws against it.

For 22 years this problem has seemed insurmountable. There have been about 100 vaccine trials since 1987, not one of them notably successful. A few years ago researchers were hopeful that a double-barreled vaccine containing antibodies against two different virus proteins might work, reasoning that HIV's mistakes in copying its genes were still pretty rare, so the chances of two happening in the same virus simultaneously was like getting hit by lightening twice - very unlikely.

The double-barreled vaccines worked well in mice, but human trials have not been encouraging. It seems people do sometimes get struck by lightening twice -- and we are talking about an awful lot of virus particles.

The last big vaccine trial, known as STEP, ended in failure in 2007. The disappointing result prompted Anthony Fauci, director of the part of NIH that funds most AIDS vaccine research, to pull the plug on current clinical trials. It was time to step back, he felt, and reassess the problem.

"We made a decision to turn the dial more towards asking fundamental questions," he said last week. "The latest (AIDS) antibody discovery," he added, "is a reflection of that shift."

Finding Broad Antibodies

In essence, here is what happened. Standing back, what is the core of the problem? The HIV virus mutates very often. So where should we be looking for a solution? Right there.

It turns out, when you step back and think about things from outside the box, that not all antibodies are the same. The AIDS virus proteins used to prepare the antibodies for a vaccine are typically bits of a HIV protein called GP120 that helps HIV latch onto cells. It turns out it makes a huge difference which bits of GP120 you use to prepare your vaccine antibody. As we have said, most parts of the virus genes accumulate changes so rapidly that the antibody offers little protection for anyone other than the person from whom the virus was isolated. The antibodies are said to be "strain specific."

But not all. Over 10 years ago, four so-called "broadly neutralizing" antibodies were isolated from AIDS patients (dubbed "bNAbs" by researchers). These four bNAb antibodies were each able to inactivate a wide range of HIV strains, and so seemed just the ticket for vaccine development. They address the core problem. In a nutshell, they are what Fauci set researchers out looking for.

So, why weren't we cheering 10 years ago? These four initial bNAbs cannot in fact be used to preparing a vaccine. They are not all that broad, and none of them is effective against strains circulating in Africa. But they point the way.

In part as a response to Fauci's call for a new look at the AIDS vaccine problem, the nonprofit International AIDS Vaccine Initiative in New York set up a project called Protocol G to look specifically for bNAbs in seven African countries, as well as four others. The IAVI provided most of the funding for the search, the NIH a smaller amount.

Here is what the researchers of Protocol G did: (1) Screening blood serum from 1,800 volunteers for anti-HIV activity (GP120 antibodies), the researchers selected the top 10 percent for full-bore analysis; (2) they extracted all the antibodies from each selected sample; (3) they then tracked down the cells that manufactured each antibody; (4) finally, they snipped the relevant gene out of those cells and cloned them.

This left them with hundreds of cell lines, each producing a pure antibody and only that antibody. In the last stage of the analysis, (5) they tested each one, searching for any that were very effective at stopping HIV viruses from attaching to a broad array of human cells.

They found two. The two new bNAbs proved to be 10 times more powerful that the four discovered 10 years earlier, and, importantly, they were both effective against African HIV strains. Both bNAbs turned out to be from the same patient (!).

These two antibodies are not themselves a vaccine, but they point the way. That they are broadly effective means that the HIV virus has an Achilles heel - a portion so essential to HIV's binding to human cells that it cannot be altered without destroying the virus' ability to infect. THAT is the target Fauci had set researchers to seek, and now it may be in their sights.

As Protocol G continues its important work, we can hope it will turn up more bNAbs, and identify one's orders of magnitude more effective. Probing HIV's weak spot with broadly neutralizing antibodies will put vaccine designers in a position, for the first time, to create a classical vaccine directed against a target that is not moving.

George B. Johnson's "On Science" column looks at scientific issues and explains them in an accessible manner. 

Johnson, Ph.D., professor emeritus of Biology at Washington University, has taught biology and genetics to undergraduates for more than 30 years. Also professor of genetics at Washington University’s School of Medicine, Johnson is a student of population genetics and evolution, renowned for his pioneering studies of genetic variability. He has authored more than 50 scientific publications and seven texts.

As the founding director of The Living World, the education center at the St Louis Zoo, from 1987 to 1990, he was responsible for developing innovative high-tech exhibits and new educational programs.

Copyright George Johnson