AIDS poses tough vaccine challenges, Baltimore says


Scientists have been working diligently for years to create a vaccine for AIDS, but they have been stymied by the fact that there is apparently no natural human immunity to HIV on which to base it. However, there has been notable progress in both treatment and research on a vaccine, according to Institute Professor David Baltimore, Ivan R. Cottrell Professor of Molecular Biology and Immunology.

In a January 17 IAP session entitled "Can There be an AIDS Vaccine?" Professor Baltimore explained that HIV is different from most other viruses that infect the body, cause an immune system reaction and then quickly run their course.

"Most viruses infect us and then go away. But HIV infects us for a lifetime, and therefore appears not to elicit an effective immune response," he said. The human body does launch an antibody response against the HIV virus, but it is slow and not productive enough to neutralize the virus, he added.

"Since HIV doesn't give good immunity, it doesn't make a good vaccine. So we may have to make a vaccine from scratch," said Professor Baltimore, who heads a program at the National Institutes of Health to develop an AIDS vaccine.

Despite the usual minuscule immune response to HIV, there is evidence that a vaccine might be possible, Professor Baltimore said. For example, some women sex workers, primarily in Africa, who have been exposed to HIV many times remain uninfected for years, but they display anti-HIV cellular immunity. And infected people rarely show signs of superinfection, although they may be continually re-exposed to HIV.

"Both are evidence that immunity exists," Professor Baltimore said. He said there also appears to be a cross-protection against HIV-1 infection in people who have been infected with HIV-2. The goal of a vaccine would be to reduce the initial multiplication of HIV and perhaps lower the infection level so people could live longer, he added.

Fistfuls of pills have been the best hope for most of those who are infected. "But taking 23 pills a day is not a way to live," said Professor Baltimore. "When I was a kid, people with polio lived in iron lungs to breathe. Now there is a polio vaccine, so there is a cure."

Even though HIV infections are leveling off, this doesn't mean the disease is going away, he said. Rather, it is endemic, or constantly present in a specific population. Some 23 million people throughout the world are infected today, and another 6.4 million have already died. In 1995 in the United States, there were 513,486 reported cases of AIDS. It is the major killer of males under age 44.

NO NATURAL VACCINE

The primary weapon against viral infections has been vaccines. Unlike bacterial infections, which usually are treated with natural antibiotics, there are no natural substances--with the exception of interferon--that can defeat viral infections, Professor Baltimore said.

Vaccine developers usually try to copy the body's natural immune process by studying people who have survived infections. Vaccines contain an antigen--a substance the body identifies as foreign--that alerts the human immune system to start up its natural defenses.

While vaccines don't limit infection completely, they do limit disease. Each time a specific virus invades the body, the immune system can in essence "recall" the virus and react more efficiently to combat disease.

But HIV, which advances rapidly into the body and also mutates rapidly over the course of an infection, has proven too deadly to use conventional techniques. Live attenuated vaccines, which use live organisms that are treated to eliminate their virulence, are considered too risky even to test in the hunt for an AIDS vaccine, except perhaps in very high-risk patients, Professor Baltimore explained.

"We need to devise ways to mimic the immunity found naturally in a live attenuated virus. We need to understand how the virus gets into the cells and possibly devise antibodies to prevent it," he said. "This requires skills in drug design that are leading-edge science."

Despite the huge challenges an AIDS vaccine poses, Professor Baltimore pointed to several AIDS research highlights in 1995-96, which he described as a culmination year for AIDS research:

  • Development of protease inhibitors as an antiretroviral therapy.
  • Discovery that the amount of virus in the blood is a predictor of the disease's progression.
  • Realization that the virus replicates at high levels all the time.
  • Discovery that chemokine receptors are co-receptors for HIV infection.

Upon infection, HIV first encounters CD4, an antigen on T4 lymphocytes, and then chemokines, which are molecules that control the growth and movement of cells. HIV attacks and kills T4 lymphocytes, which are critical to the body's immune response.

"We now know that people with a low virus replication level will get the disease very slowly or possibly never. We can detect this now. We can sequence the virus and use the information clinically," Professor Baltimore said.

He said researchers are targeting enzymes specific to HIV for possible pharmaceutical development. AZT, a drug that already is on the market, disrupts the early stages of viral reproduction by terminating the DNA chain. Drugs called integrase inhibitors that are designed to halt the progress are in development. And there are now on the market four protease inhibitors, which block viral reproduction, and a fifth is due out soon.

The federal government is giving more financial support to AIDS research, which accounted for $1.4 billion, or about 10 percent, of the $11.8 billion total budget at the National Institutes of Health in fiscal 1996, Professor Baltimore noted. The NIH appropriation for fiscal 1997 is $12.5 billion (up 6.5 percent), while the amount allotted to AIDS research is $1.5 billion, an increase of 6.8 percent.

A version of this article appeared in MIT Tech Talk on February 5, 1997.


Topics: Health sciences and technology, Biology

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