Medical researchers often keep a bottle of champagne on hand, ready for those celebratory moments when work representing years of fierce dedication can be labeled a success. Robert C. Gallo, MD, professor of medicine and director of the institute of human virology (IHV), a scientist internationally recognized as one of the most important in the world, has no such champagne stash in his office, however.
“Success is over too fast. I have to look ahead to the next challenge. There’s always something that has been overlooked, something more that needs to be done.”

So says the man who co-discovered the HIV virus, was the first to mass produce it and prove that it is the cause of AIDS, and who then went on to develop the blood test to definitively diagnose the infection.

Founded in 1996 as a partnership among the state of Maryland, City of Baltimore, University System of Maryland, and the University of Maryland Medical System, IHV formalized a 10-year relationship when it became the medical school’s first institute early in 2007. Its mission is to advance treatment and prevention of life-threatening viral diseases, especially AIDS. Its primary target, among many, is the successful development of an AIDS vaccine. That goal received formidable endorsement in the form of a $15 million, five-year grant from the Bill & Melinda Gates Foundation in July 2007.

E. Albert Reece, MD, PhD, MBA, vice president for medical affairs for the university and dean of the medical school says, “This prestigious grant again underscores the strength of the institute’s mission in channeling cutting-edge research toward the elimination of the AIDS menace.”

Strongly rooted in a translational approach in which ideas flow freely between laboratory and clinic, Gallo and associate directors William Blattner, MD, and Robert Redfield, MD, both professors of medicine, head a fully integrated program that includes clinical and laboratory research, treatment, patient counseling and outreach support, epidemiology, public health, an experimental drug initiative, and an animal model program. The three men, whose medical backgrounds are grounded in research, meet regularly to collaborate.

During the infant years of AIDS research, fears both real and imagined were widespread. No one knew how contagious the infection was. Many laboratories barred the use of AIDS samples. Gallo, then a National Institutes of Health (NIH) researcher, had to learn how to grow and mass produce the virus. His laboratory worked closely with the Centers for Disease Control (CDC) to predict its presence. The blood test he and his colleagues developed was purchased from the NIH by the government, and in 1985 brought to market and licensed to several pharmaceutical companies. The significance of that single achievement is reflected in the absence of panic that had so recently gripped the world. The likelihood of AIDS being transmitted through blood transfusion was no longer a threat. Additionally, the test made it possible to diagnose and follow patients from the earliest stages of infection, instead of losing those years the disease can take before becoming full blown.

Shortly before leaving the NIH, Gallo and his colleagues discovered the first natural molecules known to block HIV infection. Called beta chemokines, the molecules are able to prevent HIV entry into a cell. It is now known that chemokines inhibit HIV by binding to the same molecule HIV uses to enter the cell. This knowledge helped in understanding the actual receptor or doorway to HIV entry, and in 1996, led Science magazine to laud it as the most important scientific discovery of the year.

The Vaccine Search
Gallo appears to be someone understandably burdened by the demands of time and responsibility. Words come quickly because he has much to say. Clearly, he is a man driven by the clock, as well as by a self-imposed coercion to see the end of the most devastating communicable disease of the last century. Admittedly, he lacks that supposedly indispensable quality of scientists—patience. Somewhat surprisingly, however, he will break from a serious discussion of the retrovirus and exhibit an underside of wit. As for ego, he appears too busy to indulge in it.

Commenting on the institute’s progress in the development of a vaccine, for example, he says, “We don’t like to make much noise about it. Noise creates expectations we may not be able to deliver.”

“Developing any vaccine is extremely difficult,” he says. “The time and experimentation required are prolonged. There is the inclusion of regulatory agencies, the necessary alliance with a spin-off company, and the fact that, while the current climate is indeed favorable, Maryland has not always been recognized as entrepreneurship friendly.”

Those problems are compounded when attacking the HIV virus—not only because of its variation, but because it is a retrovirus that inserts itself into genes upon infection, and is in the target cell with no time to recall the immune system. At best, the immune response lasts only three to four months, and so the need for continued intensive research to sustain immunity becomes critical.
Nevertheless, the IHV team has made significant strides in overcoming such inherent obstacles. The institute has an impressive staff of developmental experts who appear to have solved the issue of variation in the virus. As for finding a start-up, IHV created its own spin-off biotech company, Profectus BioSciences, which is partnering development with Wyeth Pharmaceuticals. Right now, the outlook is promising. If all goes well, Wyeth may take on the vaccine early in 2008, and begin clinical trials in about a year. Blattner has a program ready to be tested across the country, and Redfield has established a multifaceted therapeutic research unit poised to evaluate the vaccine’s therapeutic and preventive potential.

“These are exciting times for us,” Gallo says. “Still, you don’t have a vaccine until you have a vaccine.”

Gallo became an MD because he believed it would give him a better understanding of disease, but he knew from the age of 17 that science, specifically research related to blood cells, would be his life’s work. His sister died of leukemia as a child, and he was at the National Cancer Institute (NCI), involved in virology studies aimed at leukemia, when he attended a 1982 lecture on AIDS by the CDC’s James Curran, MD. Curran’s words, “Where are the virologists?” challenged him. They also marked the beginning of his search to discover the virus, and ultimately a vaccine to prevent it.

“A few years before, in 1979, we had just discovered the first known human retrovirus, one that causes a specific kind of leukemia,” he says. “It seemed a reasonable hypothesis that the AIDS virus was a brother of that one. As it turned out, it was a distant cousin.”

Treatment: Companion to Research
Redfield’s entry on the AIDS scene followed a different path. Both his parents were NIH scientists who teased him about not being a “real” doctor when he got his MD. However, he spent 20 years as both clinician and researcher at Walter Reed Army Medical Center, where he treated numerous AIDS patients during the first years of the epidemic.

“My work has been on the edge, applying science to clinical care,” he says. “One of the problems with current AIDS treatment is drug resistance. We’re trying to attack host cell pathways, which we believe will minimize resistance. The downside of that is toxicity. We have to do it in a way that doesn’t harm the body.”

Saying that he is fundamentally a physician, Redfield warms to the subject of IHV’s treatment programs, housed in clinics and hospitals throughout the Baltimore area, with others slated to open soon in the prison system. Since Baltimore is one of two epicenters of the AIDS epidemic in the United States, and since five percent of affected Baltimore residents are in the zip code shared by the University, the Jacques Initiative, located on the medical school campus, has become a much needed community resource. The initiative is named for the late Joe Jacques, PhD, a psychologist and AIDS patient who provided counseling and support to other patients, and who left a $1 million bequest to help establish the initiative at IHV.

“Science that stays on the shelf is wasted,” Redfield says. “A decade ago, we started looking at poor success rates in treatment across the country. Our own success, while better than some, was not acceptable to us. In the beginning, we were dealing with an untreatable disease; so any success at all looked good. We became concerned because when treatment is unsuccessful, the virus becomes resistant.”

Studies showing that as much as 25 percent of newly infected virus is resistant to treatment caused Redfield to fear the resistant virus could penetrate certain populations, including substance abusers, the homeless, mentally ill, urban poor, and specific ethnic groups. There was a possibility that, 20 years hence, there would be two epidemics—one treatable, one not.

A critical underpinning of AIDS treatment is the importance of taking medications as directed. A patient who misses two out of 21 doses will fail therapy 50 percent of the time. The Jacques initiative engages people in the rigors of care before administering any medications. Both patients and families are educated and prepared for therapy. They receive support from treatment coaches, people like themselves who have been through it, who have made the same mistakes, and suffered the same consequences. Their medication regimens are monitored—every dose, every day, every week of the year. Redfield believes this kind of scrutiny, coupled with the clinic’s insistence on preparing patients for care, constitutes one of IHV’s most valuable treatment contributions to the Baltimore community.

In addition to Redfield’s clinical research and treatment in Baltimore, he heads an extensive treatment program in nine African countries, working with faith-based hospitals serving 135,000 people, 80,000 of whom are on anti-retroviral medications. The initiative, in which Catholic Relief Services is the primary grantee of funding from the President’s Emergency Plan for AIDS Relief (PEPFAR), employs the same peer support and identical education and preparation for treatment used in IHV’s Baltimore clinics. The program boasts a 70 to 90 percent success rate.

PEPFAR in Nigeria
While Redfield heads clinical programs, Blattner’s work uses broad-based and clinical research to determine HIV pathogenesis, risk factors and prevention. An oncologist who conducted epidemiology studies at NCI, he worked periodically with Gallo beginning in 1975, and became one of three founding members of IHV. He is director of the institute’s vaccine trials unit, and heads the AIDS Care and Treatment in Nigeria (ACTION) project, an international treatment program which recently received a $43 million PEPFAR grant.

“The program is a crucial one that has allowed us to set up a large affiliate in Nigeria, one that integrates public health, science and clinical research. As of now, we have provided care and treatment to approximately 240,000 people including 40,000 who are on antiretroviral drugs. We have also prevented more than 46,000 mother-to-child transmissions of HIV.”

Blattner, whose wife and four of his five children have accompanied him on trips to Nigeria, notes that PEPFAR funding covers treatment, not research. He adds that the institute has applied for an overlying NIH grant to supplement the $43 million.
NIH funding is earmarked as well for continued evaluation of the impact of HIV on the brain, looking at cognitive defects as they affect a patient’s ability to recover. “We’re studying whether the World Health Organization regimens we’re using have a positive impact on neuro- cognitive defects,” Blattner says. “Scientists at the University of California, San Diego, are highly regarded as experts in this area of study, and we’re collaborating with them, adapting their studies to West Africa.” In studying the virologic aspects associated with AIDS, the team employs epidemiology tools to develop a prospective cohort, following people for three years to see what happens to neuro-cognitive function. They then will study the pathogenesis of the virus in the brain and in the blood.

“If the virus goes into the brain, and the drug doesn’t penetrate the brain effectively, then the virus may start growing, becoming resistant to the drug and leading to the failure of therapy,” Blattner explains. “I’m bringing population factors into the design of the research by treating people who have never been treated, and following them for three years to see what happens. The samples are then sent back to Baltimore for basic research in IHV laboratories.”

This kind of research is costly and exhaustive, demanding highly skilled personnel who need to complete profiles of all the domains of mental functioning. While the studies could be performed in Baltimore, Nigeria presents a unique opportunity in that there are three sub-types of the virus in the country, allowing the team to study whether one of the sub-types is more likely than others to be associated with neuro-cognitive defects. If so, there may be neuro-virulent strains that invade the brain more easily. All this has implications for vaccine development, and the need to determine if additional vaccine components might target the sub-type of the virus in the brain.

Cross comparisons of findings from different sites will contribute to research conclusions. Walter Royal, MD, associate professor of neurology at the medical school, shares principal investigator service along with Blattner.

“This kind of collaboration creates an environment for the medical school to have an international base, one that may enhance opportunities for funding, and ultimately may have capacity for the training of medical students seeking a world view of disease,” Blattner says.

Turning back the clock just 10 years, one sees a climate of fear and ignorance surrounding AIDS. Since then, it has gone from a complex disease of unknown cause with an unequivocal death sentence, to one that, with proper treatment, can give patients many years of normal living. Yet, 22 years since the development of a simple test to diagnose HIV, 25 to 50 percent of infected Maryland residents have not been tested. So it may still be too soon for celebration.

Looking toward that day, Gallo says, “To know the world has a successful vaccine, to know this institute is responsible even partially, to see positive results—that would be a real thrill. That’s when I’ll break out the champagne.”