FREDERICK, Md. -- In the immunology lab at Stanford Hospital there was a sense of urgency to discover the culprit of the strange disease that caused rare cancers and infections, initially diagnosed among gay men. It was 1983, and the first signs of what would become the AIDS threat were outlined in a series of reports from the Centers for Disease Control and Prevention and publications in the New England Journal of Medicine in 1981.
Dr. Edgar Engleman, an immunologist and Director of the Stanford Blood Center learned of two patients that had been admitted to Stanford Hospital with the new disease. Puzzlingly, neither belonged to any of the population groups identified as being at high risk for developing it. However, both had previously undergone open heart surgery at Stanford. And both received multiple transfusions in connection with their surgery with blood from a San Francisco bank that regularly supplemented the Stanford supply.
Engleman engaged Jeffrey Lifson, M.D., an all-star quarterback at Beverly Hills High School who sped through undergrad and medical school at Northwestern University in just six years. Now Lifson was at Stanford for his residency training and joined Engleman’s cellular immunology lab for a research fellowship.
Back in his home state of California and near one of the major centers for the emerging epidemic, Lifson would soon see some of the first AIDS patients. Discoveries they made in the Stanford lab and their resolve to act on them made Engleman and Lifson pioneers in slowing the spread of the disease.
A Drive to Protect the Blood Supply
The fact that both patients had characteristic signs of the new disease but did not belong to any of the identified high-risk groups pointed to the transfused blood as the common denominator and potential route of infection.
HIV had not yet been identified as the causative agent for AIDS and thus no specific lab test was available. But it was known that a depletion of critical disease-fighting CD4+ T cells was a hallmark feature of the disease. And while the rest of the medical establishment was not ready to acknowledge this mysterious disease could be acquired through transfusion, Engleman and Lifson were more than convinced.
They adapted a research test to screen Stanford Blood Center donors for their levels of CD4+ T cells and did a pilot study. They sought to lower the risk of transmitting AIDS by transfusion by screening the donors and removing the units with CD4+T cells below the designated cutoff, all without losing a prohibitive amount of total donations.
Samples from all the blood units screened out based on the CD4 test were frozen for eventual testing with a direct assay. A year later they tested those units using the first FDA-approved HIV test and 15 came up positive for HIV.
As in modern transfusion medicine, the components of one unit of donated blood are distributed to three different recipients. “Many potential infections were averted because we were ahead of the curve,” Lifson said.
Preventing infections was important, as at the time, no effective treatment was available. Indeed, for people with gay friends, it was a devastating time as whole communities succumbed. The grief was palpable at the Stanford lab. “This was before smartphones,” Lifson said. “People would rip out whole pages of their address books and eventually just throw their address books away because everyone was dead.”
Lifson said that experience and the “annoying curiosity” to want to figure things out he’s retained since childhood led him to focus his research on seeking ways to prevent and treat this devastating disease. As he moved into the biotech industry for a while and then on to the Frederick National Laboratory, Lifson has remained at the forefront of HIV/AIDS discoveries.
Shifting the Paradigm of HIV
Early tests for HIV lacked the sensitivity to directly detect the presence of the virus in many people who had no symptoms or to determine the extent of the infection in people who tested positive.
Doctors were desperate to help patients and to evaluate the extent of their disease. Drug companies had to rely on clinical endpoints, including participants dying from AIDS, to determine if their investigational therapies were effective.
Lifson and his late colleague Michael Piatak, Ph.D. took on the challenge. They developed an assay they designated a “quantitative competitive PCR.” It was one of the first tests that could sensitively and accurately quantify HIV nucleic acids in control samples, and their laboratory validation of the technique was published in BioTechniques in 1993.
To validate the method on actual clinical specimens, Lifson and Piatak obtained patient samples from Drs. George Shaw and Michael Saag at the University of Alabama, Birmingham and conducted a blinded analysis.
Shaw and Saag were blown away when they saw the results, Lifson said. All of the patient samples tested positive for HIV, including many less sick HIV-infected patients that had scored negative with conventional tests. Levels of HIV RNA measured with the new test correlated with the stage of patients’ disease, and virus levels decreased during treatment with the antiretroviral drug AZT. The researchers authored a benchmark publication in Science in 1993.
This was a gamechanger for the HIV community. The ability to quantify the virus led to a better understanding of the disease process and assessment of investigative treatments. “Measurements of viral RNA in the blood – known as viral load testing – became a cornerstone of the drug evaluation process as well as clinical evaluation to know whether a patient was being treated effectively,” Lifson said.
By Mary Ellen Hackett, staff writer
Image: Jeff Lifson (left) has been director of the AIDS and Cancer Virus program for nearly 20 years. He’s pictured here with colleagues Brandon Keele, Jake Estes and the late Michael Piatak.Tagged: