"Gene-editing" can make immune cells resistant to HIV, and they can be safely given to patients, researchers reported.
The approach is an attempt to mimic the natural resistance to HIV found in people with a specific mutation in the gene for CCR5, a molecule the virus uses to enter target cells, according to Pablo Tebas, MD, of the University of Pennsylvania in Philadelphia, and colleagues.
But while the process was safe, most patients who then stopped HIV treatment saw their virus rebound more or less quickly, Tebas and colleagues reported in the March 6 issue of the New England Journal of Medicine.
"This is the first step ... to try to make cells resistant to HIV," Tebas told MedPage Today.
The "burden of the study," he said, is that immune cells can be modified outside the body and safely given back to patients, where they expand their numbers and persist for many months.
When HIV therapy was interrupted, Tebas said, the modified cells had a "survival advantage" compared with their unmodified cousins.
The complicated experimental trial was hailed by outside experts as exciting and notable, but with the caution that it remains unclear how the gene-editing process will fit into efforts to cure HIV.
"This is exciting stuff," commented Sharon Lewin, MD, of Monash University in Melbourne, Australia, who is co-chair of the International AIDS conference this year in Melbourne. She was also on the program committee of a major symposium on HIV cure strategies last year in Kuala Lumpur.
"You can clearly knock out CCR5 and it's safe when you put it back in," she told MedPage Today during the annual Conference on Retroviruses and Opportunistic Infections in Boston.
But, she added, it's not clear that the approach could be used to cure HIV. "I've struggled to see where it fits in the long term," Lewin said.
Indeed, other ideas for cure are getting more attention globally, she said, including such things as very early antiretroviral therapy, a "shock and kill" approach to depleting the HIV reservoir, and therapies to revive an exhausted immune system.
But the study is "an important step forward," commented Mark Kay, MD, PhD, of Stanford University School of Medicine in Stanford, Calif. and Bruce Walker, MD of Massachusetts General Hospital in Boston.
However, they cautioned in an accompanying editorial in the journal that the efficiency of the process will have to be better before it has clinical potential.
Indeed, Kay told MedPage Today in a video interview, most of the cells modified in the experiment had only one copy of the target gene changed -- not enough to make a cell completely resistant to HIV.
"To really get this to be a treatment that would really result in the potential for eradication," he said, investigators would need "to get the efficiency such that enough cells would have bi-allelic knockouts."
Tebas and colleagues worked with 12 HIV-positive people whose virus was completely suppressed by medication. They removed CD4-positive T cells from the patients and used what are called zinc-finger nucleases to edit the cellular genome.
The genetic target was the gene for CCR5, one of the co-receptors that HIV used to enter the cell.
In some people, the gene is naturally mutated -- the so-called delta32 deletion -- and if they inherit two copies of the mutation their cells are almost completely immune to HIV. Even having one copy of the mutation has been association with a slower progression of HIV.
In one notable case -- the "Berlin patient" -- a stem-cell transplant to treat leukemia yielded an apparent cure for HIV because the transplanted cells had the delta-32 mutation on both copies of the CCR5 gene.
The new study shows, Tebas told MedPage Today, that "you can do gene-editing, remove the co-receptor, and make the cells resistant to HIV."
The 12 patients, all on highly active antiretroviral therapy and without detectable HIV plasma viral loads, were divided into two cohorts. All got an infusion of 10 billion of their own modified T cells; 4 weeks later, six patients in Cohort One stopped HIV treatment for 12 weeks, while Cohort Two acted as a control group and remained on treatment.
The actual infusion appeared to be safe, with the exception of one patient who had fever, chills, joint pain, and back pain for a few days afterward, Tebas said.
In the wake of the infusion, the median CD4 T-cell count was 1,517 per cubic millimeter at week 1, up significantly (at P<0.001) from a pre-infusion median of 448, the researchers found.
After a week, the modified cells were about 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells, with a median concentration of 250 cells/mm3.
Over the longer term, the modified cells had an estimated mean half-life of 48 weeks and were detectable, Tebas said -- up to 2 years in some cases.
When the patients stopped therapy, most developed resurgent HIV viremia, the researchers reported, with the exception of one patient later found to have had one copy of the delta32 mutation in the first place.
In essence, Tebas said, "nature had done already half of the work."
In that patient, HIV viral load remained undetectable for several weeks, then spiked to 6,247 copies/ml, before declining below the level of detectability by the time therapy was re-started.
Interestingly, during the treatment interruption, the median decline in the modified cells was about 1.81 cells per day, significantly less (at P=0.02) than the 7.25 unmodified cells that were lost daily.
That suggests that the modified T cells were, as the researchers had hoped, at least partly resistant to HIV.
By itself, the gene-editing process would not lead to a cure even if the efficiency were better and more cells had both copies of the CCR5 gene knocked out, Tebas said. Instead, he envisions a "combination approach."
The first step would be to infuse completely resistant T cells. Then -- something that's still a challenge -- the quiescent cells that form the HIV reservoir would have to be activated and killed.
During that process, the modified T cells would survive and remain uninfected, while unmodified cells would be infected and die, eventually leaving only the resistant immune cells, he said. "That's where I think this approach will fit in a strategy for a cure."
The study was supported by the National Institute of Allergy and Infectious Diseases, the Penn Center for AIDS Research, the Penn Clinical Trials Unit, and Sangamo BioSciences.
Tebas disclosed relevant relationships with Sangamo, Merck, GlaxoSmithKline, Gilead, Viiv, Bristol-Myers Squibb, Tobira, Inovio, Tibotec, and Adaptimmune.
Kay and Walker disclosed no relevant relationships.
- Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner
New England Journal of MedicineSource Reference: Tebas P, et al "Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV" N Engl J Med 2014; 370: 901-910.
New England Journal of MedicineSource Reference: Kay M, Walker BD "Engineering cellular resistance to HIV" N Engl J Med 2014; 370: 968-969.