12/11/00

CHALLENGE OF THE NEW CENTURY: FINDING AN AIDS VACCINE

David Baltimore, president of the California Institute of Technology, won the Nobel Prize for Medicine in 1975.

QUESTI0N: First of all, how did HIV/ AIDS originate, and what is its global scope today?

DAVID BALTIMORE: As far as we know, HIV came from chimpanzees where it is an endemic infection, but does not cause particularly severe symptoms. In ways we may never know, it jumped into the human species, where it is highly virulent, perhaps as early as the 1930s.

It was only by the late 1970s and early 1980s that HIV became widespread and acknowledged as a new disease in the United States where medical surveillance is very good. In the United States, the rapid rise in infections plateaued, then fell significantly and remains steady at the (unacceptable) rate of 40,000 new infections a year. The picture is basically the same in Northern Europe. In Latin American levels have risen and stayed high.

Africa experienced a very rapid rise in infections, although that has fallen off in recent years -- albeit at a still very high rate. The epidemic in Africa has lasted the longest and infected so many people that the life expectancy of the worst countries have been reduced by 20 years.

The most remarkable change of late has been the rapidly rising rate of infections in Asia, with India now leading the way. And, in the former Soviet Union, though the data is unreliable because medical surveillance is so poor, the HIV infection rate is exploding.

Overall, 50 million people have been infected by HIV worldwide. 16 million have died. Thirty-four million are living with AIDS -- 4 million of those in India where the epidemic is just getting underway.

Some 15,000 people are infected daily, or 5.5 million in a year. Some 2.6 million people die each year from AIDS-related causes, making it a leading infectious disease in history on par with malaria and tuberculosis.

Q: To take the U.S. example, can't HIV/AIDS be controlled through education and drugs?

BALTIMORE: One of the great triumphs of biotechnology has been the development of anti-AIDS drugs that, in many people, can stop the infection, reverse the symptoms at least for some time, and bring those who are ill back to health.

And, yes, since we know that HIV is transmitted sexually and through sharing needles, behavioral advice, clean needle programs, condoms and even new forms of microbiosides have helped. All of these must be tried and widely implemented.

But the right way to stem HIV/AIDS once and for all would be through vaccination of the population. This is what the World Health Organization wants. It is what the World Bank wants. And, in the United States, about 10 percent of the $2 billion spent annually on AIDS research goes toward developing a vaccine.

Q: Would an AIDS vaccine be able to prevent infection?

BALTIMORE: Though we tend to think of vaccines as preventing infection, they do not. Virtually no vaccine protects against infection. What happens is that if you get infected with the virus after you have been vaccinated, then the immune system remembers that it's seen the virus previously and reacts faster and better than it would have you had not been vaccinated.

So, vaccination is a way of developing a memory, not actually providing a barrier against infection. Really, then, all vaccines prevent disease, not infection. And that's critical for HIV.

Imagine a person who's been exposed to HIV. Within a few weeks the amount of HIV in his blood starts rising very rapidly as the first indication that he's actually been infected.

At the same time the count of a key cell of the body's immune system -- called the CD4 cell -- begins to fall. And that's because HIV, which is very selective, infects those cells.

Then the virus hits a peak and its count falls enormously -- a hundredfold or a thousandfold. For a while, the CD4 cell counts come back, but the unrelenting onslaught of the virus wears them out and they slowly fall away. After years, the number of CD4 cells falls so far that the immune system can't work anymore. When that happens you start getting infected with other viruses, with bacteria, with fungi. Cancer starts occurring. And that's what actually kills people. The HIV infection probably would not be lethal were it not for all of these other things that come into play.

The battle between CD4 cells and the AIDS virus levels off at different "plateaus'' in different individuals.

One infected person may have a very high plateau, another person a very low plateau, and the variation can be a thousand fold. If the plateau is very high then the patient will get AIDS, the disease that follows from HIV, fairly soon, within the first five years or so. If on the other hand, the plateau is very low, the individual won't get AIDS for a very long time -- maybe never. And there are people below the detection threshold, many of whom have gone 20 years without showing signs of AIDS.

So, HIV is not uniformly lethal but it's usually lethal unless treated with drugs.

Now what we'd like to do with a virus is change the high plateau into a plateau so low that an infected individual can live for 20 years and maybe for a normal life span. We know many animals infected with HIV-like viruses that live a lifetime without showing symptoms. So that's not unreasonable. The question is whether we can develop a vaccine to do this.

Q: Are you hopeful that science can make such a vaccine?

BALTIMORE: Two recent experiments provide hope that it is possible to make a human vaccine for AIDS.

One is an experiment based on pure or ``naked'' DNA injected into monkeys. DNA, of course, is the hereditary material that encodes proteins. In this way, it is possible to protect monkeys against a highly pathogenic challenge.

The breakthrough here is that all vaccines developed in the past have focused on inducing antibodies to fight a virus. But antibodies don't work well against HIV, which coats itself with sugar and has other tricks that make it resistant to antibodies, making that part of the immune system of little use in fighting HIV.

The DNA treatment is a new kind of vaccine that stimulates a relatively newly discovered mechanism of the immune system --
"T-killer cells'' -- to go looking for an infected cell and to kill it through secreting a material fatal to that cell. If such a pure DNA vaccine can be developed, it can be used anywhere, including Africa. It is safe and cheap and easy to use.

Another hopeful experiment was conducted by Bruce Walker at Master General Hospital in Boston. He treated a group of gay men in the very early stages of HIV infection aggressively with drugs. Then he stopped their drug treatment and monitored them closely. To his delight, a number of his patients did not get the virus back after treatment. In those where the virus did come back, he treated them again. The virus retreated to a low level and didn't surge back.

Of course, such a course of treatment requires a level of close medical surveillance not possible for a whole society, no less across a continent with poor medical facilities like Africa.

Yet, what Dr. Walker has documented is a population of people who are controlling the virus through their own immune system. This is the first, very exciting proof that it is possible to reach a vaccine-like state in humans.

Q: Why is HIV so different than other viruses?

BALTIMORE: There are two kinds of relationships that viruses have to us -- equilibrium and non-equilibrium.

Equilibrium occurs when the virus infects people, those people transmit it to other people and others transmit it further to others as viruses have been doing for many millions of years.

When this happens the virus mutates itself to be a very comfortable part of our lives and we live with it. We generally don't die from an equilibrium virus, but get over it -- as with the common cold. There are perhaps a hundred different kinds of common cold viruses and periodically you get one of them, get well and never get that one again. You get other ones later.

There are viruses that have an equilibrium situation but in another species. In our species, they become non-equilibrium viruses to which we have not adapted.

Influenza, for example, is actually a virus of birds that periodically comes into the human population, generally through Asia. So there's constantly an influx of new flu viruses.

Ebola virus is another example of a non-equilibrium virus for humans. It is endemic to another species, probably a rodent or a bat in Africa. When it periodically gets into humans. It's devastating.

Because non-equilibrium viruses don't belong to us, their behavior in humans can be bizarre. HIV is one of those. It came into the human population from large apes. It hasn't adapted so it's still very virulent and dangerous.

No doubt, if we were willing to wait hundreds or thousands of years, maybe the virus would become less virulent as we would develop resistance, but meanwhile the devastation would be so extraordinary that it would make the plague look like a simple problem. So we can't wait. We have to develop a vaccine.

Q: So, how far off is a vaccine?

BALTIMORE: We're seeing the first light at the end of the tunnel. But right now, if I had to give advice to people who are trying to control this devastation, it would be this: Don't depend on the vaccine coming along because we simply don't know when that will be. We have to take protective measures. And I must say that I am very impressed with how many of the leaders in Africa in just the last year or two have stepped up to the plate, developed prevention programs, and, in fact, are reducing transmission levels.

(c) 2000, Los Angeles Times Syndicate International, a division of Tribune Media Services

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