Spotlight on

Jeffrey D. Lifson, M.D.

Director, AIDS Vaccine Program

Spotlight Archive

Despite much progress in more than 20 years of research, the AIDS virus (Human Immunodeficiency Virus [HIV]), remains a tremendous problem worldwide, with more than 45 million people infected, and an estimated 5 million new infections and 3 million AIDS-related deaths in 2004. The National Cancer Institute at Frederick (NCI-Frederick) has a long history of important contributions to retrovirology research and one of the largest concentrations in the country of scientists working on retrovirology and AIDS. NCI-Frederick researchers are among the world’s leaders in the search to prevent and treat HIV infection. Among these scientists is Dr. Jeffrey Lifson, who heads the AIDS Vaccine Program at NCI-Frederick.

Ironically, although Dr. Lifson never set out to study HIV and AIDS, he has spent most of his more than 20-year research career working in this area. As a medical student in 1981, he read the first reports of a new, unnamed disease in a few gay men.

Not long after, Dr. Lifson was doing his residency and a research fellowship at Stanford Medical School, with Dr. Edgar Engleman, Director of the Stanford Medical School Blood Center. Two patients, whose clinical presentations and laboratory tests fit the new syndrome, were admitted to the hospital; unlike most of the cases being reported, these patients were middle-aged individuals with none of the emerging epidemiologic risk factors for the disease. The one common denominator was that during heart surgery in recent years, both patients had received blood transfusions, from a blood bank in San Francisco, where a large population of gay men were being diagnosed with the new disease.

Today it is hard to imagine that only 25 years ago, the idea that the strange new disease could be transmitted by blood transfusion was very controversial, with most of those in the blood banking industry saying that it could not be transmitted through transfusions. Nevertheless, Drs. Engleman and Lifson concluded that the two Stanford patients represented cases of transfusion transmission and, in an effort to prevent additional cases, set up a program to screen blood donated at the Stanford Blood Bank—all this while Dr. Lifson continued his fellowship studies in basic immunology.

Since the virus had not yet been identified, no specific test could be employed to confirm its presence. However, they knew that a consistent feature of the new disease was a striking loss of one particular subset of white blood cells, called “CD4 cells” or “Helper T Lymphocytes,” and they had a state-of-the-art facility to test for these cells.

Within the first two weeks of the program, they identified a blood donor with virtually no CD4 cells. The donated blood was not used, but the donor never returned for a scheduled follow-up interview and repeat testing. A few weeks later, a physician at a hospital in Southern California told Dr. Lifson that the donor had been hospitalized with a severe case of disseminated Kaposi’s sarcoma, characteristic of late-stage AIDS.  The patient had often donated blood to San Francisco area blood banks. 

“I decided right then that maybe what we were doing with our screening program made sense, regardless of how much opposition we were receiving from other blood banks,” Dr. Lifson recalled. 

When the virus was later isolated and antibody tests to detect exposure developed, stored samples from donated blood that had been excluded by the CD4 test screening program were tested, confirming that several units from HIV-infected donors had been excluded from transfusion. In an interesting foreshadowing of later Frederick connections, the antibody tests eventually developed for screening the blood supply were developed using virus grown by Dr. Larry Arthur’s group at NCI-Frederick.

“It just goes to show how much circumstances can determine things. I got into AIDS research largely as a consequence of being in a particular place at a particular time, not any great plan or strategy,” Dr. Lifson said. 

After HIV was identified, Dr. Lifson conducted some of the early studies on how the virus interacts with its receptor on CD4 cells, how such interactions can contribute to killing the cells, and studies of the details of the immunodeficiency produced by the virus. 

In the mid 1980s, Dr. Lifson left Stanford for a biotech company, where he set up an HIV research program. Among his other activities there, working with Dr. Mike Piatak (now a researcher at NCI-Frederick), Dr. Lifson developed a new method for sensitively and accurately measuring the amount of HIV circulating in the blood, or “viral load.” Using this new test on samples provided by clinical collaborators at the University of Alabama, Birmingham, Dr. Lifson and his colleagues showed that readily measurable amounts of virus were produced at all stages of the infection, including throughout the clinically asymptomatic phase. Previously, researchers had thought that the virus remained latent, without replicating, similar to herpes viruses between outbreaks. Older, less sensitive tests could not detect the virus during the asymptomatic stage, but the more sensitive new test showed the virus was replicating continuously. This demonstration fundamentally changed understanding in the field about how the virus caused disease, with important implications for treatment. As the first potent and effective anti-HIV drug combinations eventually became available, the new viral load test was used to study the response of patients to treatment, providing additional important insights.

At first, Dr. Lifson enjoyed his stint in the biotech industry. “In a start-up company, there can be a real sense of excitement. You also have a chance, of necessity, to get exposure to areas other than basic research that you wouldn’t get involved with in a typical academic lab, such as regulatory affairs, clinical trials, GMP manufacturing and quality control.” 

While in industry, Dr. Lifson worked on collaborative projects with Dr. Larry Arthur at NCI-Frederick. Frustrated with business considerations driving research priorities, and at Dr. Arthur’s instigation, Dr. Lifson joined NCI-Frederick in 1995 to set up the Retroviral Pathogenesis Section in Dr. Arthur’s AIDS Vaccine Program. “After being in industry, it was great to be in a place where the importance and quality of the research were what mattered most,” Dr. Lifson said, noting that “Frederick is a terrific place to do research; there’s an incredible technology base, and there is a real supportive, interactive collaborative atmosphere, both among the scientists of the AIDS Vaccine Program and throughout the campus. People here are always happy to help each other out. This provides an incredible environment for our research.”

In 2002, Dr. Lifson was named director of the AIDS Vaccine Program. His work now focuses on the search for vaccines for the prevention and treatment of HIV infection and AIDS, and studies of viral pathogenesis, designed to better understand how the virus causes disease, and to define exactly what a successful vaccine must be able to do. For many of these studies, he uses an animal model that closely reproduces key features of HIV infection: experimental infection of monkeys with the related virus, Simian Immunodeficiency Virus (SIV). “We know that in HIV infection, the virus usually starts the process of overwhelming the immune system in the early stages of infection. While it can take years for infected people to develop AIDS, much of the key damage seems to be done early. We are studying these key early events, and trying to see if we can change them, using the SIV model.”

According to Dr. Lifson, “We wanted to see if by giving antiviral drugs early in the infection we could level the ‘playing field,’ giving the immune system a fighting chance by using the drugs to keep the virus from compromising the early immune response. After a few weeks of treatment, given just after the animals were infected, we found that we could stop the drugs, and most animals could control the infection very effectively, very different from what normally happens without antiviral drugs, or if the drugs are given later in the infection. They’re still infected, but they can control the virus for long periods of time, and show resistance when they are challenged again, with the same virus or with different SIV isolates.” While Dr. Lifson and his colleagues are still trying to understand the details of the immune responses that provide such striking control of SIV strains that are normally highly pathogenic, the work is providing important clues about what a successful vaccine may need to do.

Another part of his research involves a new candidate vaccine approach, developed directly out of basic science discoveries made by other AIDS Vaccine Program scientists, including Drs. Lou Henderson, Rob Gorelick, and Larry Arthur. They discovered that a protein on the inside of HIV and SIV particles is critical for the virus to be able to infect cells, and that modifying this protein, by mutation or chemical treatment, results in a virus that is no longer infectious. In a critical contrast to traditional approaches to inactivating viruses, the new chemical treatment eliminated infectivity by modifying the proteins on the inside of the virus, without affecting the proteins on the surface of the viral particles that are crucial for interactions with cells of the immune system. The chemically treated viruses thus can not infect cells, but can powerfully stimulate immune responses to the virus. So far, early tests with the vaccine approach in monkeys are encouraging, but according to Dr. Lifson, even if this type of vaccine ultimately is not effective, the fact that it is a very valuable reagent for studying how the virus interacts with cells of the immune system will have made the work invested worthwhile.

Two decades of working on AIDS have given Dr. Lifson a deep appreciation of the process of evolution and the power of natural selection. “Studying this virus is like watching evolution in action. It has a limited amount of genetic material to work with, but it uses an error-prone mechanism for reproducing itself to generate lots of mutants. Most are unsuccessful, but if it makes enough mutants, chances are that one or another will have properties that allow it to better escape from any given immune response or drug treatment, and mutant viruses having these properties are then rapidly selected. This process allows the virus to rapidly adapt to changing environments. It is both humbling and a proof of the power of this ‘random’ process that so far it has thwarted the combined best efforts of the research community. Like the bumper sticker says, ‘Nature always bats last.’”

Dr. Lifson continued, “Development of an effective vaccine for HIV poses scientific challenges beyond those that have been faced in the development of any of the vaccines currently in use. Despite the challenges, I feel very fortunate to be able to do this kind of work, and to do it in the unique environment at Frederick. Basically, science consists of asking questions about how things work, and then trying to think of clever ways of posing those questions experimentally so that you can force Nature to give you an answer. I find this process intrinsically gratifying, but knowing that some of the answers we find may have the potential to help with a problem as important as AIDS makes it all the more satisfying. It is just frustrating sometimes that the research seems to progress so much more slowly than the pandemic.”

Dr. Lifson also observed, “One of the great things about working here is that we have, as an explicit part of our mission, a mandate to collaborate with researchers outside of Frederick, sharing the reagents and testing methods we develop here. It is a great feeling to know that things that you have developed for your own work can also help others in their studies, advancing the field more rapidly. Plus, it is a great way to get involved in lots of interesting collaborations!” 

In another interesting twist, Dr. Mike Piatak, mentioned earlier, now works with Dr. Lifson in the AIDS Vaccine Program, where they have developed a state-of-the-art viral load test for SIV that is crucial to their pathogenesis and vaccine work, and is provided as a service to researchers across the country.

Dr. Lifson continues to work hard to fight the virus that he says “for 25 years has managed to stay ahead of a lot of smart people.” The National Cancer Institute is fortunate to count Dr. Lifson among its prominent young scientists. And given his track record so far, it is conceivable there will be many more accomplishments in store as he continues to work within the NCI-Frederick community.

“For someone like me who likes asking and answering questions, doing science is the perfect job. In contrast to many jobs, in science, if you are bored, it is probably your own fault for not asking interesting enough questions!”

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