Temple Magazine

New Pathways

Recent research at Temple sheds light on certain white blood cells that might help the scientific community get closer to the development of an HIV/AIDS vaccine.

Story by By Mark Wolverton
Photos by Joseph V. Labolito

Even when he was 8 years old, Jay Rappaport knew he was going to be a scientist: He proclaimed it in a short biography he wrote as a school assignment.

Written in pencil on a single sheet of lined paper, the document now hangs on the wall in Rappaport’s office in the new Medical Education and Research Building at the Health Sciences Center. His mother framed it and presented it to him when he graduated from the University of Pennsylvania with a PhD in microbiology. “I didn’t even know she’d kept it,” he admits.

More than 20 years later, Rappaport is still a scientist and a dedicated researcher who has devoted most of his career to battling one of nature’s most complex killers: HIV/AIDS.

Now a professor of neuroscience and neurovirology, director of the biomedical neuroscience graduate program and associate chair of the Department of Neuroscience at Temple University School of Medicine, Rappaport has been on the front lines of the HIV/AIDS fight since 1987.

Toward the Center

Fresh from graduate school and a postdoctoral fellowship at the Wistar Institute, a biomedical research organization, Rappaport went to work in the laboratory of Robert Gallo, one of the co-discoverers of HIV. There, he studied the workings of the virus at the molecular level and the structure of its proteins with an eye toward the eventual development of a vaccine.

After his early work with Gallo and stints at the National Institutes of Health (NIH) in Bethesda, Md.; University of California, San Diego; and Mt. Sinai Hospital in New York City, Rappaport returned to Philadelphia to form the Center for Neurovirology at Hahnemann University Hospital with Kamel Khalili, chair of the Department of Neuroscience and director of the Center for Neurovirology at Temple. Neurovirology comprises several related disciplines, including neurology, virology and molecular biology, to study viruses that invade and affect the nervous system.

In 1999, the center relocated from Hahnemann to Temple as part of the College of Science and Technology. Now part of the School of Medicine—a hub for NIH-funded protocols and clinical trials in neurodegenerative and neuromuscular diseases—the center researches the neurological effects of conditions such as HIV/AIDS, Alzheimer’s disease, multiple sclerosis and Parkinson’s disease.

It is routinely ranked in the top 15 of all neuroscience departments for NIH funding. And recent NIH funding will establish the new Institute for Translational Neuroscience.

A Different Approach

Though HIV/AIDS is sometimes eclipsed in the general consciousness by recent disease outbreaks such as H1N1, the virus remains a global threat. In 2009, the Joint United Nations Programme on AIDS and the World Health Organization estimated that 33.4 million people around the world are living with HIV. The organizations’ report, AIDS Epidemic Update, also estimated 2.7 million new HIV infections and 2 million deaths from the disease in 2008, indicating that advances in treatment, preventive methods and education are still urgently needed.

Rappaport’s interest in AIDS pathogenesis—the way the disease takes hold in the body—and how it manifests in the central nervous system set him on a new research path. “I believe that the general immune dysfunction in AIDS and the disorders that are found in the central nervous system [in AIDS patients] are linked,” he says.

The common mechanism, he believes, involves monocyte macrophages, a type of white blood cell subverted by HIV when it infects a person. By zeroing in on these alternate pathways to AIDS infection, Rappaport has forged another way to understand and deal with HIV, providing invaluable clues to a part of the puzzle.

When HIV invades the body, it attacks certain cells of the immune system, infecting and changing them so they no longer perform their normal function of destroying foreign cells.

Jay Rappaport and Michael Kogan, a graduate student in the School of Medicine, discuss Rappaport´s research in the Department of Neuroscience laboratory.

Gabrielle Lehmicke, an associate researcher in the Department of Neuroscience, examines brain scans in the department laboratory.

One of the virus’s main targets is a set of white blood cells that fight infection called CD4+T cells. A drop in the number of these cells below a certain critical level in the bloodstream signals the transition from HIV infection to full-blown AIDS—the point when the immune system is no longer able to defend the body.

Since the 1980s, a great deal of HIV/AIDS research has concentrated on CD4+T cells, the deterioration of which is used to mark the progress of the disease. However, Rappaport focuses on macrophages, which normally attack and consume invading microbes. “Macrophages are a major reservoir for HIV infection that remains unaddressed right now,” he says.

Some monocytes (a type of white blood cell) leave the bloodstream to enter the body’s tissues, where they differentiate into macrophages. Macrophages also stimulate the responses of lymphocytes that combat specific pathogens. Rappaport and his research team at Temple discovered an altered subset of these monocyte macrophages that sharply increases in patients with HIV.

“We were able to correlate the expansion of this subset with increases in viral load. At the same time, we found that the subset expands in relationship to how low the CD4 count is,” he explains. In other words, as the virus multiplies, the population of monocyte macrophages increases, while the number of CD4+T cells decreases. These HIV-infected macrophages cause trouble in the central nervous system.

“They accumulate around blood vessels and they secrete not only virus, but also some inflammatory cytokines that cause damage to the nervous system,” Rappaport says. “Cytokines” are proteins that communicate with cells, causing them to react to the signals cytokines send.

“We think that what happens early in infection is, the virus enters the central nervous system through the invasion of inflammatory cells—probably infected macrophages, possibly some T cells,” he explains. The immune system can clear the actively replicating virus from the body early on. But late in the disease, he says, the subset accumulates in the circulatory and central nervous systems.

This finding contradicts an earlier “Trojan horse” model commonly held among most researchers, which proposed that HIV-infected macrophages enter the nervous system immediately upon infection and lie dormant for a time, emerging later to re-infect the body. Instead, Rappaport says that diseased macrophages are activated, enter the circulatory system and are transported to the nervous system to invade it.

Learning more about the effects of HIV-infected macrophages on lymphocytes could provide significant insight into how the infected cells compromise the immune system.

Aiming for a Vaccine

Treatment for HIV/AIDS has slowly evolved since drugs such as AZT were first made available in 1989. Since the late 1980s, more than 30 possible vaccines have been tested. None have succeeded.

But Rappaport believes that targeting this altered set of monocyte macrophages can lead to new therapeutic treatments and to a vaccine. “There has to be a way to get the immune system to eliminate them or to target specific survival pathways to enable them to undergo cell death,” he says. “I hope that the work we’re doing in trying to investigate the pathogenesis of AIDS in the central nervous system will lead us back to how to generate an effective vaccine.”

In July, Rappaport was awarded a five-year grant from the NIH/National Institute of Mental Health. The next step of his research will be to “bring the changes in the central nervous system disease together with changes in the immune system,” he explains. “We’re going to look at changes in monocyte macrophage dynamics and at their rates of production, and see how that correlates with changes in immune function. I think it will provide good groundwork for some of the therapeutic studies.”

After almost a quarter-century of fighting HIV/AIDS, Rappaport believes that a cure—or at least a vaccine—is now within reach.

“I think we’re almost there,” he says. “We’re able to extend people’s lives, control the virus and stay ahead of its mutations by multiple drug therapies.” But, he adds, “It’s a matter of time and effort and some creativity to come up with something that really works. We need some new approaches and some new ideas.”

Mark Wolverton is a freelance writer whose work has appeared in various national magazines, such as Air & Space/Smithsonian and Popular Science.

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