The New York Times - November 20, 1984
Harold M. Schmeck Jr.

These viruses are called retroviruses. Some of them have been known since the early 1900's as causes of cancers in chickens and other animals. They have been much-studied over the years because of the clues they offer to the nature of cancer and even to the basic organization of life.

In addition to their newly discovered role in some human diseases, retroviruses seem to be the most promising prospect for use as vehicles to transplant genes from one species to another. As such, genetically engineered retroviruses may become agents of future attempts at human gene therapy. Some experts believe the first such attempts may come within two years. In the past few years some of the retroviruses have been analyzed down to the ultimate molecules of their genes. Important clues have been collected on the specific means by which they cause cancer and why some of them do this with terrible swiftness while others take a large part of a lifetime. But the viruses continue to cause surprises. One of the greatest surprises was the discovery that some retroviruses have been able to kidnap genes from animal cells and reintroduce them through infections, setting up the circumstances that can lead to cancer. Only in recent years has the name retrovirus been applied to the viruses. The name comes from the virus's most characteristic and unusual trait, the possession of an enzyme, called reverse transcriptase, that reverses the flow of genetic information normal to all living things.

In all animals, plants and microbes, DNA (deoxyribonucleic acid) is normally the archive of genetic instructions for every cell. It determines what each cell can become and every product that it will be able to make.

The messages of this genetic archive are then translated into the form of another nucleic acid, RNA (ribonucleic acid), which actually serves as the blueprint from which the cell makes its products. This progression from DNA to RNA to the manufacture of proteins has been called the central dogma of molecular biology.

Reverse transcriptase, as the name implies, reverses an important element of the process and translates the message of RNA into the form of DNA. The core of each retrovirus is composed of two identical strands of RNA. The enzyme makes it possible for the genetic blueprints embodied in these strands to be translated into DNA in cells infected by the virus. After this, the cell can be induced to manufacture new virus particles or their parts. Perhaps even more important, the DNA copy of the virus's genes can become a permanent part of the cell's genetic endowment.

The discovery, about 15 years ago, of reverse transcriptase and the chemical process the enzyme carries out has had pervasive effects on modern research in molecular biology. For this discovery, Dr. David Baltimore of the Massachusetts Institute of Technology and Dr. Howard Temin of the University of Wisconsin won a Nobel Prize in 1975.

Since then, the reverse transcriptase has become a key tool in many aspects of biological research, and the retroviruses themselves have become central to much of the study of cancer. Retroviruses have been a key to the discovery and understanding of oncogenes, the particular genes of animals and humans that appear to play a role in the process by which cancer originates. These genes are thought to have normal functions in regulating cell growth and development, but they seem to contribute to the cancer process when activated too much or too little, when they are put in the wrong place within the genetic apparatus, or when a mutation has changed such a gene's chemistry.

"Basic cancer research with viruses has proved directly relevant to human cancers by identifying genes which can lead to cancer when several of them are altered in one cell," Dr. Temin said earlier this year in testimony before a Congressional subcommittee. "This identification provides targets for therapy and means for diagnosis and perhaps prevention."

Many Species Are Affected

Beginning in the early years of this century, scientists have identified more and more viruses that can cause cancers in such diverse species as fowl, mice, cats and nonhuman primates. More recently it has been discovered that many of these viruses are equipped with reverse transcriptases.

The inner core of an ordinary retrovirus contains three genes called pol, gag and env, as well as flanking sequences of RNA that are crucial to the process by which the virus genetic material is activated to subvert the cell it invades. Pol is the gene for the reverse transcriptase enzyme, gag is the gene for the virus's internal proteins, and env is the genetic code message for production of the virus's outer envelope.

Some of the retroviruses also carry an oncogene picked up originally from an animal cell and incorporated permanently in the virus. Sometimes these genes replace part or all of one of the other genes. Sometimes the oncogene is simply an addition.

Scientists have discovered that those retroviruses that have oncogenes are usually the ones that produce deadly cancers in animals most rapidly, sometimes within only a few weeks. Some of the other retroviruses also cause cancer, but usually at a far slower rate.

Suspected in Human Disease

Because of the wealth of evidence linking various retroviruses with cancers in animals, many scientists thought one or another such virus must be a factor in some human cancers, too. Many different viruses were suspected, but none stood the test of thorough research. Meanwhile, other viruses totally unrelated to retroviruses were shown to be probable factors in some human cancers, although probably not the direct and sole cause.

Notable among these were some herpes viruses linked to cervical cancer; a herpes virus called the Epstein Barr virus linked to a kind of lymphoma especially in parts of Africa and to nasophryngeal carcinoma in Asia; and the hepatitis B virus, linked to liver cancer in parts of southern China and Southeast Asia.

But, the class of retroviruses, which included the first known cancer viruses of animals, still could not be tied clearly to any human cancer.

HTLV-1 Reported by Gallo

The break came about 1980 with the publication of reports by Dr. Robert C. Gallo's group at the National Cancer Institute linking some leukemia and lymphoma patients with what appeared to be a retrovirus. These were cancers of important white blood cells called T-lymphocytes. The virus was named human T-cell leukemia- lymphoma virus. It is now known as HTLV-1 and has been linked particularly to cancers in a region of southern Japan. The virus has been found in many areas of the world including the United States, the Caribbean region and Africa. It is generally regarded as the first cancer-causing human retrovirus.

A closely related virus called HTLV-2 has also been found in one cancer patient and in one chronic drug abuser, but has not yet been linked conclusively to human disease, Dr. Gallo and Dr. Samuel Broder of the National Cancer Institute said in an article in the Nov. 15 issue of The New England Journal of Medicine. The scientists said the genes of both viruses have been cloned and analyzed, and they do not have oncogenes. Nevertheless, they can transform cells growing in the laboratory into a cancerlike state.

A third member of that family of retroviruses, HTLV-3, is considered to be the cause of AIDS. A virus linked to AIDS discovered by scientists in France and named LAV is now generally believed to be identical to HTLV-3.

Linked to Non-A Non-B Hepatitis

One of the greatest recent surprises in retrovirus research was the report a few weeks ago implicating something resembling one, in a puzzling category of hepatitis infections.

A group led by Dr. Robert J. Gerety of the Food and Drug Administration found evidence of reverse transcriptase activity in blood serum samples known to have transmitted what is called non-A non-B hepatitis. This hepatitis includes most of the liver disease transmitted by blood transfusion. It has been called non-A non-B because the two known hepatitis viruses, hepatitis A and hepatitis B, have been ruled out as causes. Neither virus resembles retroviruses.

As described by Dr. Gerety, the discovery of reverse transcriptase activity in non-A non-B hepatitis was to some extent a consequence of two earlier discoveries, the link between HTLV-1 and cancer, and, particularly, the relationship of HTLV-3 to AIDS.

The scientists at the F.D.A. were concerned over the possible risk of transmitting the AIDS virus with material used to test for the presence of antibodies against that virus. In testing human material for such use the scientists found clear evidence of reverse transcriptase activity. They also found related evidence including particles visible under the electron microscope that looked like retroviruses.

Other Diseases Are Suspect

The link to hepatitis still remains to be confirmed.

Nevertheless, Dr. Gerety, as well as many other scientists, thinks we have by no means heard the last of retroviruses in human disease.

"That should be obvious," Dr. Gerety said. "I think there are a lot of chronic human diseases" for which there are no known causes and for which one or another of the ominous retroviruses should make excellent candidates.

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