Fighting the AIDS Virus at Harvard

High above the street, in Massachusetts General Hospital's Grey Building, behind steel double-doors and space-age airlocks, scientists are busily searching for the "cure" to a deadly disease that may kill hundreds of thousands before it is conquered. The malefactor is Acquired Immune Deficiency Syndrome, known as AIDS.

Dr. Martin S. Hirsch and his colleagues at the Harvard-affiliated hospital also work in other, ordinary medical research laboratories, eschewing what Hirsch calls such needlessly elaborate facilities. In the regular labs, they search for a sensible way to control the illness--not for some magical super-cure.

Beneath commonplace Laminar Flow Hoods and in hospital examination rooms. Hirsch, an associate professor of medicine, is diligently directing a two-pronged quest for an AIDS remedy. "The most important questions from a clinician's point of view are how can you treat it and how can you prevent it," Hirsch says, and that is exactly what he is trying to do. By developing drugs to knock out the AIDS virus, and by determining why some infected patients die while others live, he hopes to move toward a solution to a problem that has galvanized the nation.

AIDS, first reported in the U.S. in 1979, is a disease that breaks-down the body's natural immune response system and leaves its victims open to opportunistic infections and cancers. Additionally, patients with AIDS frequently develop mental illnesses, such as dementia or meningitis, caused by the AIDS virus. Scientists believe at present that AIDS is caused by a virus similar to herpes called Human T-Lymphotrophic Virus Type III (HTLV-III) which infects the white blood cells. But while the virus has been linked to AIDS, it does not always produce the deadly and debilitating disease. Sometimes, it causes a milder illness known as AIDS-Related Complex (ARC) or has absolutely no effect.

The official tally of AIDS cases nation-wide was 20,766, as of Monday, nearly twice what it was one year ago. So far 11,384 people have died after contracting the illness. AIDS has been primarily associated with gay men, intravenous drug users and people who need frequent blood transfusions. By unofficial estimates, the number of ARC cases could range as high as 50,000, and the number of asymptomatic carriers--those who have been infected but have not displayed symptoms--could be as high as 2 million. No one is known yet to have recovered from AIDS.

A "Cure"

While molecular biologists like Dr. William Haseltine and Dr. Myron E. Essex (See profile below) have probed the HTLV-III virus to discover its fundamental building blocks, others in the Harvard Medical Area like Hirsch at Massachusetts General and Dr. Jerome E. Groopman at New England Deaconess Hospital are hunting for immediate ways to stop the disease.

Their studies involve both patients and test-tubes and their methods are aimed at producing a panoply of weapons "that would be effective in eradicating or at least controlling this virus in patients," Hirsch says. Groopman, an assistant professor of medicine, concurs, saying he has never worked so hard in his life to catch the "clever sucker."

Four approaches to the disease now look most promising. The two doctors and their teams want to develop anti-viral drugs to treat infected patients, engineer antibody-based vaccines to ward off the disease, elucidate how the virus attacks the body, and discover what "cofactors"--or additional factors--cause some people infected with the virus to contract full-blown AIDS while others go unaffected.

Treatment

Two anti-viral drugs are on the cutting edge of Hirsch and Groopman's research. They are azidothymidine (AZT), a synthetic drug that was originally designed to combat cancer, and alpha interferon, a relatively new, genetically-engineered substance. Hirsch has just concluded a two-year placebo-controlled, double-blind study of 24 AIDS and ARC patients treated with the interferon, whose results will be revealed in June. In addition, both Hirsch and Groopman are participating in a nation-wide study of AZT in AIDS and ARC patients. Hirsch has already enrolled more than 100 patients, while Groopman is in the process of selecting 20.

When HTLV-III invades the body it infects certain white blood cells and, possibly, other cells vital to the body's defense and maintenance. The primary target known to scientists is the T-helper lymphocyte, called "the general" of white blood cells because it helps orchestrate the body's defense. The AIDS virus entwines itself in the fundamental genetic material at the cell's nucleus, where it uses the cell's own mechanisms to reproduce many-fold. The viruses then destroy that cell and escape to invade others.

Scientists hope AZT will interrupt this process by preventing the HTLV-III virus from latching onto the genetic material and multiplying, while they hope alpha interferon will keep the viruses from leaving the white blood cell and attacking others. Hirsch is hopeful about the two drugs, both of which have already been shown effective in the laboratory. But there are some indicators that AZT may hold more promise, he and others say.

Unlike alpha interferon, AZT can pass through the blood-brain barrier and counteract HTLV-III viruses that have invaded the brain. This may be vital to any successful anti-viral substance that is developed, Hirsch says, because otherwise the virus will simply sequester itself in the brain, the spinal cord, and the peripheral nerves. However, he says that alpha interferon--which is known to be useful in combatting some AIDS-related cancers--may prove valuable in combination with other anti-viral drugs. "[AZT] may turn out to be more useful," he says, "although I don't think we should jump to any premature conclusions."

However, AZT has disadvantages of its own, says Dr. Richard G. Marlink, a research fellow in Groopman's laboratory. To be effective AZT must be taken orally every four hours continuously. "Even if it's having any effect, it may be something a patient will have to use the rest of his life," Marlink says. Still, alpha interferon and AZT, are the two most promising drugs around at present, better than those researchers--including Groopman--have tested before such as the much-touted suramin, Marlink says.

Still other problems plague the researchers in their quest for an effective and non-toxic anti-viral drug--some of them not involving science. Groopman has encountered peculiar problems in the AZT study. "There is tremendous political pressure," Groopman says. He only has room for 20 patients while 60 AIDS and ARC patients want to take part in the experiment. So he will choose patients only on a "first-come, first serve basis."

The two laboratories are also trying to arrest the disease before it gains a foothold in a larger segment of the population by developing vaccines which would help protect the body from infection. (See story below)

Cell Biology

Because so little is understood about how HTLV-III attacks the body, much of today's clinical research is directed at determining exactly how the virus interacts with the white blood cells. Both Hirsch and Groopman are involved in this basic work, labelled cell biology.

To most questions, now, the answer is still, "We don't know," but Groopman says they are making progress. The most recent discovery came out of both laboratories simultaneously, and may lead scientists to an understanding of how the virus damages the neurological system.

Both Groopman and Hirsch have found in laboratory tests that HTLV-III attacks not only the T-helper lymphocytes, but also another type of white blood cell, called a macrophage, that has been linked to cells in the brain. The macrophage or disease-fighting white blood cell is not killed by the virus, Groopman says, but instead is used as a breeding ground.

Hirsch adds that it is possible that the virus is carried to brain by the macrophages, but is unsure how this will effect the search for a treatment. "Macrophages can support the replication of this virus," he says. "Whether this will affect the future of anti-viral studies, it's too early to tell."

Cofactors and Cohorts

Hirsch and Groopman are also eagerly looking into other critical questions about the nature of AIDS. Who gets it and why? Who dies and who lives? How is the virus transmitted?

Hirsch is currently conducting a study of cofactors to determine whether the effect of the HTLV-III virus is exaggerated by certain lifestyles or diseases that target the immune system. For nearly four years, Hirsch and his MGH team have been following 170 gay men in the Boston area, seeing them at regular three-month intervals. This study, begun before scientists had discovered HTLV-III, was originally designed to determine the cause of AIDS. Although they have not yet formulated any conclusions, Hirsch says they will continue to study cofactors, placing special emphasis on the herpes group viruses which often infect AIDS patients.

Groopman has begun a similar study of how AIDS is spread, involving as many as 500 patients over the course of three years. He plans to look at AIDS patients and their partners to determine what cofactors may be involved.

Other reseachers including Dr. William Haseltine, however, are skeptical about cofactors. "In my personal opinion, the cofactor issue has yet to be proven," he says.

Another area of AIDS research Hirsch is examining is transmission of the HTLV-III virus. HTLV-III is only known to be transmitted by contaminated blood and semen. Researchers have not yet determined whether the virus can be transmitted by female genital fluids, although Hirsch has found evidence that such fluid may contain the virus. The virus can, however, be transmitted from mother to unborn child, by contaminated needles and transfusions. Since April 1985, blood banks have screened blood donations for signs of the virus.

"We would like to see whether female to male transmission can be demonstrated conclusively," Hirsch says of the future. "We would like to see how new-borns become infected, and how often they do become infected."