Of Vaccines, Treatments and Screenings

Every few months doctors from medical research centers seem to announce another major breakthrough in the search to cure AIDS. Standing before a group of anxious reporters, the doctors explain in layman's terms the genetic and protein makeup of the AIDS virus which has the popular reputation as one of the deadliest diseases known.

Since the first American AIDS case was diagnosed in 1979, doctors have made the Harvard Medical Area one of most important centers for AIDS research in the world. A group of them has been responsible for pioneering work in the way the virus reproduces itself. Another group has discovered relatives to the AIDS virus.

But connecting these complex medical discoveries to an actual cure is another matter. Harvard researchers hope their work will pave the way to either a vaccine, which would keep people from being infected, or a drug, which would help kill or control the AIDS virus. Their work is also devoted to developing tests to catch people who are carrying the virus and determining how many of them will actually get sick.

However, the road to a cure or preventive treatment for AIDS may well be a long one, Harvard researchers say. "We have a lot of work to do," says Dr. William Haseltine, who directs AIDS research at the Harvard-affiliated Dana-Farber Cancer Institute. "We have to be prepared for the long haul. We should make plans to work on this systematically for 10 to 15 years."

The AIDS virus is called Human T-Lymphotrophic Virus Type III (HTLV-III) in America. And Harvard doctors seek to unravel the genetic and protein makeup of the virus. The work is particularly rewarding because at every turn the researchers seem to discover something which writes a new chapter in biology textbooks.

Haseltine's research focuses on the genetic structure of the AIDS virus. "We analyze the virus' DNA sequence to get a blueprint on what the virus can do," explains Haseltine, who is an associate professor of pathology at the Med School. His lab has found a number of unusual genes on the AIDS virus including the tat-gene which makes it possible for the AIDS virus to replicate many times faster than the average virus, and the art-gene which regulates the virus' speed of reproduction.

Dr. Myron E. Essex directs an effort at the School of Public Health studying the proteins in the virus and the antibodies produced in reaction to the proteins. His group has discovered several viruses related to HTLV-III which may be useful for developing a vaccine.

Vaccine

Harvard researchers spend much of their time trying find ways to apply their discoveries to an AIDS vaccine.

However researchers say that a vaccine may not be viable because of several major problems associated with the HTLV-III virus.

In some cases, people infected with HTLV-III don't develop any immune response at all, and some people who do develop antibodies aren't even protected by them. Since vaccines work by stimulating protective antibodies, there is some question whether a vaccine could work effectively.

"There is a serious question whether human beings make any sort of protective response at all. Nobody can predict whether it will be easy or hard to make a vaccine," Haseltine says.

But Essex, who is a professor of microbiology at the School of Public Health postulates, "It is extremely likely that we'll know within a year whether a vaccine is feasible."

Essex studies the proteins which make up the virus and tries to determine which "structural parts of the virus are biologically significant." From his studies of HTLV-III relatives, "We hope to find a weakened form of the virus. The analogy is to smallpox and cowpox. Cowpox is harmless, but [exposure to it] is protective against smallpox," Essex says.

Earlier this spring, Essex and some researchers in Senegal, Africa, discovered that a large portion of the human population had been infected with a close relative of the AIDS virus. HTLV-IV, as the researchers dubbed the new virus, infects some human white blood cells, just like the AIDS virus, but with one crucial difference--the AIDS virus kills the white blood cells and HTLV-IV does not. Essex says he hopes to "use molecules from HTLV-IV to create a protective response" from the human immune system.

However, injecting people with a virus similar to AIDS is not the only kind of vaccine possible. In another approach, doctors insert part of the HTLV-III virus, like the virus' envelope or shell, onto the harmless portion of another virus. When that new half-breed virus grows, will have the HTLV-III shell without the virus' deadly properties. Then the human immune system may be able to develop protective antibodies to the AIDS virus by coming into contact with a harmless, "dummy" AIDS virus created in the lab.

"I think that approach is what will be done first," Haseltine says.

Drug Treatments

AIDS researchers haven't put all of their eggs in the vaccine basket, however. Some doctors, Haseltine among them, are also trying to design a drug treatment program for AIDS patients.

Haseltine's discovery of the tat-gene may prove to be extremely important in the drug development process. Without the tat-gene the virus can't grow, so if researchers can find a chemical which interferes with the workings of that gene, or any other essential virus process, they are well on their way toward finding a drug treatment program.

"The ideal drug stops some virus enzyme from working but doesn't interfere with normal cells," Haseltine says. So, the more doctors know about how the virus works, the more opportunities they have to stop it from functioning properly.

"This virus presents a plethora of targets because it's not a simple retrovirus. The more we know about it, the more complicated it is," Haseltine says. "It's like the difference between a cowboy's coffee not and an expresso maker: they both make coffee, but one comes with all those bells and whistles, so it's a lot easier to mess up. [The AIDS virus] comes with a lot of genetic baggage which might provide theraputic targets."

Chemically creating a drug which stops a specific viral function, a method called rational drug design, is not the only way researchers go about looking for a chemical cure for AIDS. Haseltine's lab is also helping to design a drug screening program.

Drug screening programs test tens of thousands of chemicals, first in the lab, and then in animals, to find a drug which might cure or arrest AIDS. The possiblities are gradually narrowed down as a chemical meets or fails to meet a set of criteria.

Even after scientists find drugs which can cure or arrest the AIDS virus, they face additional challenges. In order for the drugs to work patients will probably have to take a lot of them over a long period of time. Therefore researchers have to worry whether the chemicals could harm the body over the longterm. "We must imagine lifelong high dose therapy to keep the virus continually suppressed. We have to think about what those chemicals will do to the liver and kidneys," Haseltine says.

However, the outlook is not completely grim. Although Haseltine says he thinks finding drugs to treat AIDS will take time, he remains optimistic. "We are where cancer chemotherapy was in the 1950s. We have drugs that are beginning to work."

Finding Out Who Has It

But in order for the drugs to work, doctors have to be able to determine who has AIDS as soon as possible. "It's like the early detection of cancer. If we were to use the drugs at the very earliest stages of the disease, the chances of success are greater," Essex says.

So workers in his laboratory spend a great deal of time trying to apply their knowledge of the viral proteins to developing better diagnostic and screening tests for AIDS.

And these diagnostic tests will be in use quite soon, according to Essex. "We already have some tools to categorize whether people are likely to be sick. It's a question of polishing. Within a year we'll have them tested and polished," he says.

Essex's lab is also working to develop a more sensitive AIDS screening test. The test currently in use screens the blood for antibodies to the AIDS virus. That procedure presents certain difficulties; there is a lag time "between infection and the presence of antibodies of two to three months, but the individual still has the virus," Essex says. "We need to look for earlier markers."

Haseltine predicts that this venture will be a success. "Within a year there will be more sensitive, more accurate tests," he says.