AIDS Virus Findings Offer Hope for Drug Development

Scientists have discovered that HTLV-III, the virus that causes AIDS, uses a surprisingly novel mechanism to genetically control the cells it invades, and they say this finding opens the way for the development of new kinds of anti-AIDS drugs.

In an interview, Dr. William A. Haseltine of Boston’s Dana-Farber Cancer Institute said the discovery represents an “advance in fundamental biological knowledge” that he believes will have broad applications in fields other than AIDS, especially for the new science of genetic engineering.

Haseltine and his colleagues describe their findings in a report published today in the British journal Nature.

Their work sheds light on the means by which genes, the units of heredity, regulate the manufacture of thousands of proteins that are necessary for life.

Specifically, the finding involves a particular protein, called the transactivator, that is manufactured by cells infected by HTLV-III.

In previous studies, Haseltine and others have learned that the transactivator greatly accelerates the production of HTLV-III virus components by an infected cell.

This means that when it is properly triggered, the cell suddenly begins making new HTLV-III viruses at an enormous rate and releases them so that they infect new cells.

This comes about because the viral gene responsible for making the transactivator becomes integrated into the cell’s own genetic material at the time that the virus invades the cell. In this way the virus gains control over the cell’s gene regulatory system and uses it for its own purposes.

Controlling the Protein

It has been known for some time that cells control the amount of protein made by a gene in two different ways.

One way involves regulating the number of molecules--called “messenger” RNAs--made from a given segment of genetic material. The messengers are an interim step in the production of protein.

The other method involves increasing the amount of protein that is made from each messenger molecule.

According to Haseltine, all biological research to date has shown that almost all cells control the amount of a protein that they manufacture by regulating the number of messengers they make.

But HTLV-III has been found to be almost unique in that it controls the amount of transactivator manufactured by stepping up the amount of protein made by each messenger molecule.

The researchers found that infected cells were able under proper circumstances to increase the amount of transactivator 1,000-fold above normal, thereby allowing large numbers of viruses to be replicated.

The experimental drugs currently used to combat HTLV-III have been designed to interfere in various ways with the more conventional mechanism used by cells to regulate protein.

The discovery that HTLV-III uses an unusual mechanism of gene regulation should help in the design of anti-viral drugs aimed at interrupting the processes, Haseltine said.

Haseltine said the discovery has fundamental biological significance because it shifts much of the attention of biology from the nucleus of a cell, the place where genes are located, to the cytoplasm, which is outside the nucleus and is the place where many of the processes involved in virus replication are located.

“We now realize there is an excess capacity in cells to translate RNA (genetic material) into protein and that it increases the production a thousand-fold outside the nucleus,” he said.

“All the attention for the past 30 years has been on the nucleus. We are now moving into outer-cell space.”

Haseltine believes that this new type of gene control discovered in HTLV-III probably is used by other genes as well--and not just by virus genes.

“The type of regulation observed for transactivator of HTLV-III is likely to prove to be a prototype for a new class of cellular regulatory events,” he said.

“HTLV-III has brought to us the gift of knowledge, but at a terrible price.”

The spinoff to genetic engineering, he said, will be to use what has been learned from HTLV-III to increase the quality and the production of pharmaceuticals and other products now being manufactured by means of recombinant DNA techniques.

Haseltine has been at the forefront of research on retroviruses, the class of virus to which HTLV-III belongs, since 1977, when he began working with Dr. Robert Gallo, the co-discoverer of the acquired immune deficiency syndrome virus.

Earlier in his career, he worked in the laboratory of James D. Watson, co-discoverer in the 1950s of the structure of DNA. That discovery led to the intensive scientific interest in the cell nucleus as the site of gene regulation.

Co-authors of Haseltine’s latest study were Dr. Craig A. Rosen, Joseph G. Sodroski, Wei Chun Goh, Andrew I. Dayton and Judith Lippke.