Science / Medicine : RETROVIRUS: : AIDS Research May Yield Cure for a Family of Related Diseases
It was only a decade ago. The medical community was feeling quite secure. It had stamped out smallpox, put a hold on polio, held tuberculosis at bay. Vaccines and antibiotics had saved us from bacterial and viral infections; wide-scale epidemics were now a topic for history books.
But the picture changed drastically in 1981 when doctors first diagnosed a patient as having AIDS. A new disease had appeared on the horizon, an illness caused by a contagious agent now known as a retrovirus. The new epidemic took many off guard.
Aside from AIDS, small-scale epidemics caused by related retroviruses emerged in isolated regions around the world. These cousins of the AIDS virus carry the blame for some forms of cancer and neurological disorders.
Thus far scientists have found no cures for any human retroviral diseases. They have concentrated their efforts on studying AIDS, for which few treatments are available.
But the knowledge they gather in the search for a cure for AIDS is likely to provide a strong foundation for understanding and treating other retroviral disorders.
The unique viruses contain the preface “retro” because they act in a reverse direction. In all known organisms, the genetic material DNA is converted to RNA and then to proteins. In these “backward” entities, however, the hereditary information is carried by RNA, which is translated backward to DNA. The resulting DNA then infects the host cell, incorporating itself into the host’s genetic material where it can later replicate.
In 1910, Peyton Rous identified the first retrovirus and found that it could cause tumors in chickens. During the next 70 years, scientists continued to study these pathogens in other farmyard creatures such as mice, cows and cats. Retroviruses, they learned, were clearly linked to cancer. If the pathogens could induce malignancies in animals, scientists reasoned, why not also in humans?
But by the late ‘70s, no one had been able to isolate a retrovirus from humans. Many researchers were beginning to doubt that any type of virus was involved in cancer. The virus cancer program at the National Institutes of Health had closed down. Convinced that retroviruses were unique to animals, many believed retroviral research should be scaled back.
However, in 1979, Dr. Robert Gallo of the National Cancer Institute proved the skeptics wrong when he identified the first human retrovirus, human T-cell lymphotrophic virus-1 (HTLV-1). Victims carrying the virus suffered from a rare cancer: adult T-cell leukemia (ATL). Since HTLV appeared to affect only a small segment of the population, the discovery didn’t receive much attention in the press. Scientists identified the first cluster of patients on two southern Japanese islands: Kyushu and Shikoku. Later, more cases surfaced in the Caribbean, parts of South America and Africa.
The disease remained in small, circumscribed regions for a specific reason. Unlike common cold viruses, which can be sneezed from carrier to carrier, HTLV followed a more selective route of infection: by blood transfusions, sexual contact or from a pregnant woman to her growing fetus. Once transmitted, the pathogen could hibernate in the victim’s cells for as long as 40 years before symptoms appeared. Then the cancer began. Specialized blood cells, called T4 lymphocytes, would proliferate wildly. Patients were overwhelmed by fatigue and deteriorated quickly, dying within three to four months.
At the time, the discovery of HTLV seemed inconsequential to the public. Adult T-cell leukemia touched the lives of few people in the United States. Two years later, however, the rise of AIDS changed public indifference. The fatal syndrome contained many similarities to HTLV-linked leukemia.
The parallels to ATL were striking. AIDS infection, as with ATL, often occurred years before symptoms manifested themselves. The disease was transmitted sexually, through blood or from a mother to her unborn child. The syndrome also produced abnormalities in the same cell population, T4 lymphocytes. However, in AIDS, the infectious agent destroyed massive quantities of blood cells. In contrast, with ATL, those same T4 lymphocytes exploded in a cancerous growth.
“It just seemed too coincidental that all those things fit,” Max Essex of the Harvard School of Public Health said. A related virus must be involved in AIDS, he and many of his fellow scientists believed. With the discovery of HTLV, the tools had been developed to study human retroviruses. Now scientists could use these tools to quickly track the infectious agent responsible for AIDS. As anticipated, a retrovirus, known today as human immunodeficiency virus (HIV), turned up as the cause of AIDS.
After Luc Montaigner of the Pasteur Institute and Gallo isolated HIV, blood tests were developed which detect exposure to the virus. Scientists purified and grew the pathogen. They identified the individual building blocks from which it is made and determined the sequence in which these components assemble. Researchers have investigated the virus and how it interacts with the host environment. Only one major step remains: to find a cure.
Once found, a remedy for AIDS should have positive ramifications beyond the disease itself. If and when researchers succeed in designing a drug to fight AIDS, they can then use the same concepts to synthesize drugs against other retroviral infections. As members of the same family, all retroviruses share traits with the AIDS virus. And since concerted efforts are being directed against AIDS, any cure will most likely originate there. “If you have any glimmer of hope . . . of treatment,” Hilary Koprowski of the Wistar Institute said, “then it would come from AIDS (research).”
To which other diseases does Koprowski refer? There are a variety caused by a handful of different retroviruses. The picture has only begun to unfold in this field.
“In this field, it’s almost like one virus begets another,” Dani Bolognesi of Duke University Medical School commented. “When you have the information about one . . . you have the tools to look for relatives of that virus. And the more viruses you have, the more chances you will have of finding relatives to these.”
In 1982, just before HIV was identified, Gallo and David Golde of UCLA isolated the second human retrovirus. Because of its similarities to the first cancer virus, it was named HTLV-II to distinguish it from the original HTLV-I.
HTLV-II causes a less severe cancer. Though the disease is uncommon, it seems to be spreading among intravenous drug users. In addition, there is recent evidence indicating that when infection with HTLV-I or II couples with HIV, AIDS progresses more rapidly than with HIV alone. A second AIDS virus, known as HIV-II, has also been identified in West African patients.
Scientists have established a firm relationship between virus and disease with the HTLV and HIV viruses. The former causes leukemia and the latter leads to AIDS, but other, grayer areas exist where a fragile connection to retrovirus is slowly emerging.
Koprowski has been investigating one of these diseases. He is using HTLV to trace a retroviral link to multiple sclerosis. The neurological disorder has perplexed scientists for more than half a century; Koprowski hopes that retroviruses may provide some answers.
Both Koprowski and another team of researchers have found fragments of the HTLV virus in blood cells of multiple sclerosis (MS) patients. Koprowski believes they are looking at a relative of the leukemia virus. However, the virus associates with a different type of white blood cell in MS than in leukemia. In MS, retrovirus targets blood cells called monocytes, whereas in leukemia, the virus attacks lymphocytes.
Not all in the scientific community accept the validity of these results. They say the virus test is overly sensitive and could be detecting simple contamination from the laboratory. That is not holding Koprowski back however. He feels retroviruses may provide a long-sought key to explain many diseases of the central nervous system.
“I think we are entering a completely new era of viral research in chronic neurological diseases,” he said. Aside from MS, other related disorders have produced solid links to HTLV-I. Tropical spastic paraparesis (TSP) is prevalent on tropical islands including Jamaica and Martinique in the Caribbean, Tumaco off the Pacific Coast of Colombia and the Seychelles in the Indian Ocean. Evidence of the virus linked to TSP has also turned up in the same Japanese regions where scientists detected the original leukemia (ATL). Patients with TSP develop weakness and numbing in their legs. They also experience a tingling, pins-and-needles sensation in their feet, accompanied by lower back pain.
Until more concrete data is produced, however, no one claims to have found the cause of multiple sclerosis. Koprowski says he will now probe the brain, looking for evidence of viral infection in this well-sealed structure.
If retrovirus is present in brain cells, researchers must then determine how the pathogen attacks its prey. Does it actually penetrate brain cells, or do infected monocytes attack the nervous system? Maybe the new virus invokes an immune mechanism which alters brain cells. Before these questions are answered, the cause of multiple sclerosis will still be subject to debate.
Only a decade ago, many thought retroviruses were only a laboratory curiosity unique to animals and non-existent in humans. But since Gallo first identified the cause of adult T-cell leukemia, the list of human retroviruses has continued to grow. There are two relatives in the HTLV family and now a companion for the original HIV. Claims are also being made about an additional member of the HTLV group, for now called HTLV-5. And Gallo promises there will be at least one more in 1989, though he cannot elaborate at this time.
In 10 years, causes for old diseases have been found while new disorders have surfaced. Thus far, scientists have been unable to control this new class of infectious agents. And no one knows for sure how many additional human retroviruses scientists will find. What is known, however, is that the different viruses have many common characteristics. Once scientists have learned to tame one single retrovirus, they will have the tools to conquer others. A cure for AIDS may well provide answers for all retrovirus-based disease.
