University Of Chicago Professor Wins $50,000 Bristol-Myers Squibb Award For Distinguished Achievement In Infectious Disease Research

November 05, 1998

Bernard Roizman, Sc.D., the world's leading expert on herpes simplex virus (HSV), and Joseph Regenstein Distinguished Service Professor in the departments of molecular genetics & cell biology and biochemistry and molecular biology at the University of Chicago, has been named the winner of the eighth annual Bristol-Myers Squibb Award for Distinguished Achievement in Infectious Disease Research. Dr. Roizman mapped the genome of HSV, described how the virus infects host cells and later developed recombinant DNA techniques that have enabled him and others to determine the role of specific genes in viral infection and replication. Dr., Roizman's work has laid direct ground for current efforts to develop a vaccine against HSV, as well as for gene therapies and anti-cancer treatments that employ altered forms of the virus.

"Bernard Roizman's studies of herpes viruses over the past three to four decades have largely defined this field," says Peter Palese, Ph.D., chairman of the Department of Microbiology at the Mount Sinai School of Medicine in New York. "He has been and remains a towering figure and intellectual force in virology and in biological science in general."

"Dr. Roizman's contributions to both our knowledge of viruses and the science of genetic engineering have been fundamental," says Richard Colonno, vice president, Infectious Disease Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute. "He exemplifies the qualities that the Bristol-Myers Squibb award is meant to honor."

In the late 1950s, Dr. Roizman pioneered in purifying the DNA of HSV and describing its unique structure. One of his most important findings was that gene sequences in HSV differ in unrelated people, but are identical in related people with the virus.

**With Genetic Fingerprints, Dr. Roizman Creates "Molecular Epidemiology"

The discovery of these "genetic fingerprints" opened the door to a new science that Dr. Roizman termed "molecular epidemiology"--literally, the ability to trace HSV infection from person to person. Wielding this new tool, Dr. Roizman was able to show that nurses in hospital maternity wards were unwittingly passing HSV from infant to infant simply by failing to wash their hands between handling children. His study demonstrating this led directly to a change in hospital practices and a dramatic decrease in HSV transmission in maternity wards.

With the advent of recombinant DNA technology in the early 1970s. researchers gained the ability to insert or delete specific genes in many organisms and thus learn the gene's function. But the genome of HSV was too big for manipulation in the laboratory, so Dr. Roizman's group induced the virus itself to cut and paste genes into its own DNA.

"We found that if we put a piece of DNA with some homology [genetic similarity] to HSV into a cell infected by the virus, about one in a thousand viral particles would acquire the DNA and integrate it into its genome," Dr. Roizman explains. "We came up with a technique to select for the particles that would do that, and that eventually gave us the ability to make insertions and deletions at will."

Others have since used this technique to explore the genomes of pox viruses, adenoviruses and large DNA insect viruses. Dr. Roizman himself has used it to identify at least some of the functions of all 84 HSV genes--in particular how they enable the virus to infect host cells and then use the host's reproductive machinery to replicate itself.

**Unchecked Virus Enters Sensory Neurons

The virus initiates the infection process at the body's "portals of entry"--mouth and genitals--at which point it can still be treated and cured. Unchecked, however, it climbs the nerve trunk and inserts itself into the sensory neurons, where it remains in latent form, waiting for another opportunity to reinfect the original sites of attack. No treatments have yet been devised to eradicate HSV from the body once it has entered the sensory neurons.

"Unlike HIV, HSV has no intention of killing its host--in fact, it wants to ensure the survival of the host so that it will continue to replicate," Dr. Roizman says. The virus behaves differently, however, in different environments. In some people, it exists only in latent form. In others, it triggers mouth or genital sores. And in one in 250,000, for reasons as yet unknown, it penetrates the blood-brain barrier, entering the central nervous system, where it causes encephalitis.

**Protease Enzyme Essential to Replication

In describing the role that HSV's genes play in these processes, Dr. Roizman found products of several that are essential to replication--including a protease enzyme that many pharmaceutical companies are currently testing as a target for an anti-herpes drug.

"But the genes that aren't essential to replication are equally as important as those that are," he says. "They create an environment in which the virus can replicate efficiently. They let the virus take over the host cell system, and enable it to survive in humans."

Much like HIV, what HSV does to host cells is like "converting an entire department store to sell only one kind of hairpin," Dr. Roizman says. The virus totally changes the machinery of the host cell, while also ensuring that the host will be unable to mount any resistance (for example, it blocks signals that would cause the cell to respond to the invader or alert the body's white blood cells to a foreign presence.)

"It's amazing," he says. "The virus is so much smaller than the host cells, yet it has so many mechanisms to take them over."

In manipulating the genes of HSV to learn their function, Dr. Roizman has also devised ways to harness the virus' unique survival abilities to fight other diseases. For example, HSV can use enzymes produced by certain kinds of cancer cells. Dr. Roizman was able to create an attenuated "brain safe" form of HSV that lacks the virus's natural ability to cause damage to the central nervous system, but which still retains the ability to seek out cancer cells, use their enzymes to grow, and ultimately, destroy them. He also demonstrated that an altered form of HSV can be safely used as a "vector" for the expression of foreign genes--in other words, that genes from other organisms can be implanted in the virus, and that those genes will express their natural protein products. Researchers at Georgetown University and the University of Alabama at Birmingham are now conducting Phase I clinical trials in which they use modified HSV to destroy malignant gliomas (incurable brain cancers that occur in about 10,000 patients each year).

The infectious disease grants and awards program is one of six biomedical research grant programs funded by the Bristol-Myers Squibb Foundation. The others support research in cancer, cardiovascular/metabolic disease, the neurosciences, nutrition and orthopedics.

Bristol-Myers Squibb is a diversified, research-based health and personal care company whose principal businesses are pharmaceuticals, consumer products, nutritionals and medical devices. The company also is a leader in consumer medicines, orthopedic devices, ostomy care, wound management, nutritional supplements, infant formulas and hair and skin care products.
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University of Chicago

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