Gene therapy locks out HIV, paving the way to control virus without antiretroviral drug

March 5, 2014

University of Pennsylvania researchers have successfully genetically engineered the immune cells of 12 HIV positive patients to resist infection, and decreased the viral loads of some patients taken off antiretroviral drug therapy (ADT) entirely—including one patient whose levels became undetectable. The study, appearing today in the New England Journal of Medicine, is the first published report of any gene editing approach in humans.

The phase I study was co-authored by researchers at Penn Medicine, the Albert Einstein College of Medicine and scientists from Sangamo BioSciences, which developed the zinc finger nuclease (ZFN) technology, the T cell therapy approach used in the clinical trial.

"This study shows that we can safely and effectively engineer an HIV patient's own T cells to mimic a naturally occurring resistance to the virus, infuse those engineered cells, have them persist in the body, and potentially keep viral loads at bay without the use of drugs," said senior author Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at Penn's Perelman School of Medicine. "This reinforces our belief that modified T cells are the key that could eliminate the need for lifelong ADT and potentially lead to functionally curative approaches for HIV/AIDS."

June and his colleagues, including Bruce L. Levine, PhD, the Barbara and Edward Netter Associate Professor in Cancer Gene Therapy in the department of Pathology and Laboratory Medicine and the director of the Clinical Cell and Vaccine Production Facility at Penn, used the ZFN technology to modify the T cells in the —a "molecular scissors," of sorts, to mimic the CCR5-delta-32 mutation. That rare mutation is of interest because it provides a natural resistance to the virus, but in only 1 percent of the general population. By inducing the mutations, the scientists reduced the expression of CCR5 surface proteins. Without those, HIV cannot enter, rendering the patients' cells resistant to infection.

For the study, the team infused the modified cells –known as SB-728-T—into two cohorts of patients, all treated with single infusions—about 10 billion cells—between May 2009 and July 2012. Six were taken off antiretroviral therapy altogether for up to 12 weeks, beginning four weeks after infusion, while six patients remained on treatment.

Infusions were deemed safe and tolerable, the authors report, and modified T cells continued to persist in the patients when tested during follow up visits. One week after the initial infusion, testing revealed a dramatic spike in modified T cells inside the patients' bodies. While those cells declined over a number of weeks in the blood, the decrease of modified cells was significantly less than that of unmodified T cells during ADT treatment interruption. Modified cells were also observed in the gut-associated lymphoid tissue, which is a major reservoir of and a critical reservoir of HIV infection, suggesting that the modified cells are functioning and trafficking normally in the body.

The study also shows promise in the approach's ability to suppress the virus. The viral loads (HIV-RNA) dropped in four patients whose treatment was interrupted for 12 weeks. One of those patients' viral loads dropped below the limit of detection; interestingly, it was later discovered that the patient was found to be heterozygous for the CCR5 delta-32 gene mutation.

"Since half the subject's CCR5 genes were naturally disrupted, the gene editing approach was building on the head start provided by inheriting the mutation from one parent," said Levine. "This case gives us a better understanding of the mutation and the body's response to the therapy, opening up another door for study."

Therapies based on the CCR5 mutation have gained steam over the last six years, particularly after a man known as the Berlin Patient was "functionally" cured. Diagnosed with acute myeloid leukemia (AML), he received a stem cell transplant from a donor who had the CCR5 mutation in both alleles (from both parents) and has remained off ADT since 2008. Researchers are attempting to replicate this phenomenon because allogeneic transplants—which carry a high mortality risk and require lengthy hospitalizations—are not a practical solution for HIV patients who do not have blood cancers. Nor are they effective in ridding the body of HIV unless the donor has the mutated gene in both alleles, as shown recently in two Boston patients who were thought to have been "functionally" cured from transplants, only to see their spike.

Though disappointing to the research community, the Boston patients' results highlight key factors when combating the virus.

"Those cases emphasize the need to protect T cells from the virus," said Pablo Tebas, MD, director of the AIDS Clinical Trials Unit at the Penn Center for AIDS Research, one of two centers where the study was completed. "The Boston cases show us that for the Berlin patient, it was not the chemotherapy or infusion of a donor's stem cells that staved off the HIV; it was the protection of the T cells by the lack of CCR5. Those procedures couldn't completely eliminate the reservoir of the HIV virus, and when the virus came back the T cells were susceptible to infection. The ZFN approach protects T cells from HIV and may be able to almost completely deplete the virus, as those cells are still functional."

Further clinical trials will evaluate greater numbers of modified T cells in a larger cohort of patients, as well as strategies to increase the persistence of more in the body to achieve a therapeutic effect.

Explore further: Gene therapy reduces HIV levels in small trials

Related Stories

Gene therapy reduces HIV levels in small trials

September 20, 2011
(Medical Xpress) -- This weekend at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, Illinois, researchers from two different study groups, one on the east coast and one on the west coast, ...

HIV cure hopes dashed for two US cancer patients (Update 2)

December 6, 2013
The latest hopes of curing AIDS were dashed Friday when US researchers said HIV returned in two men who briefly eradicated the virus after bone marrow transplants for cancer.

Study identifies population of stem-like cells where HIV persists in spite of treatment

January 12, 2014
Although antiviral therapy against HIV suppresses viral replication and allows infected individuals to live relatively healthy lives for many years, the virus persists in the body, and replication resumes if treatment is ...

NIH study describes new method for tracking T cells in HIV patients

February 3, 2014
A team of researchers has reported a novel method for tracking CD4+ T cells in people infected with HIV. CD4+ T cells are critical for immune defense against an array of pathogens and are a primary target of HIV. In the study, ...

Immune cells engineered in lab to resist HIV infection

January 22, 2013
Researchers at the Stanford University School of Medicine have found a novel way to engineer key cells of the immune system so they remain resistant to infection with HIV, the virus that causes AIDS.

Bone marrow transplant eliminates signs of HIV infection

July 26, 2012
Two men with longstanding HIV infections no longer have detectable HIV in their blood cells following bone marrow transplants. The virus was easily detected in blood lymphocytes of both men prior to their transplants but ...

Recommended for you

Paris spotlight on latest in AIDS science

July 21, 2017
Some 6,000 HIV experts gather in Paris from Sunday to report advances in AIDS science as fading hopes of finding a cure push research into new fields.

Scientists elicit broadly neutralizing antibodies to HIV in calves

July 20, 2017
Scientists supported by the National Institutes of Health have achieved a significant step forward, eliciting broadly neutralizing antibodies (bNAbs) to HIV by immunizing calves. The findings offer insights for HIV vaccine ...

Heart toxin reveals new insights into HIV-1 integration in T cell genome

July 20, 2017
Human immunodeficiency virus (HIV)-1 may have evolved to integrate its genetic material into certain immune-cell-activating genes in humans, according to new research published in PLOS Pathogens.

Scientists capture first high-resolution image of key HIV protein transitional state

July 13, 2017
A new, three-dimensional snapshot of HIV demonstrates the radical structural transformations that enable the virus to recognize and infect host cells, according to a new study led by scientists at The Scripps Research Institute ...

Barrier to autoimmune disease may open door to HIV, study suggests

July 11, 2017
Researchers from the University of Colorado School of Medicine have discovered that a process that protects the body from autoimmune disease also prevents the immune system from generating antibodies that can neutralize the ...

Team tests best delivery mode for potential HIV vaccine

June 20, 2017
For decades, HIV has successfully evaded all efforts to create an effective vaccine but researchers at The Scripps Research Institute (TSRI) and the La Jolla Institute for Allergy and Immunology (LJI) are steadily inching ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.