Stories of Hope: HIV/AIDS

We have come a long way in our ability to help people infected with HIV, the virus that causes AIDS. Antiretroviral therapy, using a combination of HIV medicines, means the disease can now often be managed as a chronic condition. But many researchers are still working on developing a cure, so that people no longer need to take medications to control their HIV.

CIRM has funded four different clinical trials targeting HIV. These use a similar approach, taking the patient’s own blood forming stem cells and genetically “editing” them to either block the ability of HIV to infect cells, or boost the patient’s own immune system to fight back against the virus.

Dr. John Zaia and a team at City of Hope and Sangamo Therapeutics is genetically modifying patients’ blood forming stem cells to functionally cure people with HIV. The team is using a technology called zinc finger nucleases – a kind of molecular scissors – to snip out the target gene that codes for the CCR5 receptor. This receptor is the gateway for the HIV virus into immune cells. The hope is that this treatment will provide a renewable, long-lasting source of HIV resistant immune cells in patients.

Dr. Steve Deeks and a team at the University of California San Francisco (UCSF) is conducting a clinical trial that modifies a patient’s own immune cells in order to treat and potentially cure HIV. The team will take a patient’s blood and extract T cells, a type of immune cell. The T cells are then genetically modified to express two different chimeric antigen receptors (CAR), which enable the newly created duoCAR-T cells to recognize and destroy HIV infected cells. The modified T cells are then reintroduced back into the patient. The goal of this one-time therapy is to act as a long-term control of HIV with patients no longer needing to take ART, in effect a form of HIV cure. This approach would also address the needs of those who are not able to respond to current approaches, which is estimated to be 50% of those affected by HIV globally.

A team at UC Davis, led by Dr. Mehrdad Abedi, is taking a patient’s blood forming stem cells and inserting three anti-HIV genes into them and then returning them to the individual to help rebuild their immune system. The anti-HIV genes are then passed on to all new immune system cells, which makes them resistant to HIV. Because AIDS-related lymphoma is linked to the constant immune cell stimulation caused by HIV infection, getting rid of the virus should prevent return of the cancer.

Read about CIRM funding for HIV/ADS research

Watch the Spotlight on HIV/AIDS talks

CURING HIV/AIDS

Call it molecular jujitsu.

The human immunodeficiency virus that causes AIDS is a wily adversary, evolving around opponents enlisted to defeat it. But researchers at City of Hope in Duarte, Calif., led by John Zaia, M.D., intend to employ the strength of the virus against itself, the way jujitsu practitioners leverage an enemy’s force to shape his downfall.

The lynchpin in this strategy is the protein CCR5, which makes a doorway HIV uses to enter an immune cell. Individuals resistant to HIV have a mutation in the CCR5 gene. German researchers “reinvigorated the field,” Zaia said, with a paper in the New England Journal of Medicine in 2009 about a stem cell transplant using cells from an HIV-resistant donor. The transplant not only successfully treated the patient’s myeloid leukemia, but cleared his HIV as well. Since the treatment, doctors have been unable to detect any HIV in the patient using even the most sensitive tests.

Because of the odds against finding a matching donor with the CCR5 mutation for every person with HIV, the paper didn’t show the way to a cure. But it did highlight the hope of stem cell transplants. Zaia will use stem cells to create HIV resistance with the help of molecular scissors—an engineered molecule called a zinc-finger nuclease, a technology developed by Richmond, Calif., company Sangamo BioSciences Inc.

Zinc “fingers” are peptides selected to bind to a specific area of DNA. The fingers grab a targeted sequence and sever it. Normally, the CCR5 protein snakes through the cell membrane in a series of hairpin curves. But cut the CCR5 gene, and the protein no longer appears on the cell surface; HIV’s entryway disappears like a vanishing door in a Harry Potter novel.

To make the door fade forever, the gene must be disabled in a patient’s stem cells, which will hand the mutation down to future cell generations. Animal studies show that only a fraction of the stem cells need the CCR5 mutation to create disease resistance. Whereas other genetic engineering approaches must alter great numbers of cells to create lasting change, and must keep those new cells running for a lifetime, the jujitsu nature of the zinc-finger approach means the zinc fingers must operate only briefly, mutating only a small percentage of all the stem cells.

Animal studies show HIV’s killing efficiency becomes its undoing, jujitsu style. The disease attacks the unmutated cells. The survivors all carry the mutation, and the virus has no one to plunder. Viral levels fall.

“There is a need for improved treatment of HIV/AIDS,” Zaia says. “The zinc-finger technology offers real promise.”