Last Tuesday, on World AIDS Day, VICE aired its HIV special report “Countdown to Zero” on HBO, an hour-long documentary that focused on some promising scientific advances—including one happening right here at Penn Medicine—that are putting us steps closer to a vaccine and a potential cure.
Decades in the making, Penn’s breakthrough—spearheaded by Pathology and Laboratory Medicine professors Carl H. June, MD, and Bruce Levine, PhD, and Pablo Tebas, MD, director of the AIDS Clinical Trials Unit at the Penn Center for AIDS Research—became well known last year when the team published a New England Journal of Medicine article that garnered significant public, scientific and media interest.
It was the first report of any gene editing approach in humans, where T cells from HIV patients were genetically manipulated using so-called “molecular scissors” to lock out the virus and keep their viral loads at bay—without any antiretroviral drug therapy (ADT), the standard medications for HIV patients.
Sitting down for an interview at the Henry A. Jordan Medical Education Center earlier this fall, June took host Shane Smith through the science and provided some important context for the continuing gene editing work at Penn.
“All the textbooks say HIV is incurable,” June said in the episode, “but there is one patient now that the scientific world accepts had a late stage infection and is now cured.”
June was talking about Timothy Ray Brown, a man known as the “Berlin Patient,” who was “functionally” cured in 2008. Diagnosed with acute myeloid leukemia while studying in Germany (Brown is American), he received a stem cell transplant from a matched donor who was also selected because they carried a very special mutation known as CCR5, one that only 1 percent of the population harbors—including Penn’s own James Hoxie, MD, an HIV researcher in the Penn Center of AIDS Research.
The mutation is important because it wouldn’t let the virus in Brown’s body penetrate his T cells and destroy them. Without T cells to invade, the virus is now undetectable in blood and biopsy samples.
“What we did is try to replicate this by using the patients’ own bone marrow system and then making it HIV resistant, by gene editing,” June said.
For their clinical studies, the team takes out the patients’ blood, and, in the laboratory, uses the “molecular scissors,” known as zinc finger nucleases, to cut out the area of the genome with the CCR5 gene. That happens in the Clinical Cell Vaccine Production Facility, which is a “clean” lab located in the Hospital of the University of Pennsylvania.
In the episode, Levine gave a tour of the facility where this delicate procedure happens. Everyone donned a full Tyvek suit, mask, booties, and latex gloves to prevent any contamination to the cell samples being analyzed and manipulated.
“What you are doing here is a recreation of what happened in the ‘Berlin patient’ who had the CCR5 mutation?” Smith asked Levin before they headed in. To which Levine replied: “Exactly.”
After that process is complete, the engineered cells—about 10 billion cells—are then infused back into the patient. The results so far? Clinical studies continue with the group, but their latest published results in the NEJM article were very promising.
The study showed that they can safely and effectively engineer an HIV patient’s own T cells to mimic the mutation and keep viral loads at bay without the use of drugs. They successfully genetically engineered the immune cells of 12 HIV positive patients to resist infection, and it was observed that the viral loads of some patients taken off antiretroviral drug therapy entirely decreased from peak levels. One patient’s levels even became undetectable.
CCR5 is an important mutation, but it’s not the only mutation associated with HIV infection. It has a lesser known, but potentially very important cousin: CXCR4. It’s another HIV co-receptor used by the virus to enter and infect T cells. Some researchers believe it may make even more T cells resistant to the virus and thus re-invigorate the immune response to control HIV replication in the absence of ADT.
This mutation wasn’t covered in the VICE episode, but at the Penn CFAR, investigators recently began studies looking at CXCR4, building upon the success of past CCR5 studies that utilized the ZFN technology. Led byJames L. Riley, PhD, an associate professor of Microbiology, the studies—a mix of preclinical and clinical studies—are being fueled by a $7.5 million grant from the National Institutes of Health.
Tebas, Hoxie, June, Michael C. Holmes, PhD, VP Research at Sangamo BioSciences Inc., E. John Wherry, PhD, a professor of Microbiology and director of the Institute for Immunology, and Frederick D. Bushman, PhD, a professor of Microbiology, are also part of the team.
Instead of ZFN technology, the researchers will use a personalized immunotherapy technology—now used in cancer—to safely build up a set of modified, HIV-1 resistant T cells in HIV infected patients.
“This is an important component of the HIV gene therapy work here at Penn, as it will tell us how these approaches stack up against each other,” Riley said. “We are ultimately trying to find effective, lasting ways to eliminate the need for lifelong ADT for HIV infected patients, and we believe these projects will help find the answers to some of the hard questions surrounding that goal.”
As the VICE episode points out, we’ve come far in the fight against the disease, but we still have far to go.
You can check out the full VICE episode on HIV here.