Helping T-cells block HIV with gene therapy

HIV needs to use different receptors before it can get inside a cell. These receptors are found on the surface of a cell. The first receptor that HIV needs is called CD4. After attaching itself to CD4+ cell, HIV then needs one of the following two co-receptors to gain entry:

• CCR5 or CXCR4

HIV that prefers to use the CCR5 co-receptor is called R5 tropic and HIV that prefers to use CXCR4 is called X4 tropic. Some types of HIV use both co-receptors; these are called dual or mixed tropic (D/M).

Researchers in Berlin, Germany, have successfully carried out stem-cell transplants in an HIV-positive man who had cancer. The donor from whom the cells were harvested had what researchers call the delta-32 mutation. People with this rare mutation do not express CCR5 receptors on their cells. This mutation renders them only partly resistant to HIV infection—they can still be infected by X4 strains of the virus. Because the Berlin patient now appears to be cured of HIV, researchers in other parts of the world think that interfering with cells’ ability to express CCR5 might duplicate the success of the Berlin patient in other HIV-positive people.

The Sangamo Biosciences Corporation has developed a genetic therapy that suppresses the formation of CCR5 receptors on CD4+ cells. For this therapy, CD4+ cells are first extracted from an HIV-positive person. The cells are taken to a laboratory where they are infected with a harmless modified virus that carries genetic material and instructs cells to stop producing CCR5 receptors. The specific virus used in these experiments is called an adenovirus and generally does not cause harm to humans. In the lab, the infected cells are stimulated to make copies of themselves. These copies are then infused back into the HIV-positive person.

Sangamo funded a clinical trial to test the safety and preliminary effectiveness of this therapy in San Francisco. Safety studies are very important for genetic therapies, as there is the potential that such therapies may inadvertently trigger the development of tumours.

In a study with nine male HIV-positive volunteers, different participants received the following doses of modified cells:

• 3 people – 500 million to 1 billion cells
• 3 people – 2 billion cells
• 3 people – 3 billion cells

The average profile of participants when they entered the clinical trial was as follows:

• age – mid-50s
• CD4+ count – between 270 and 450 cells
• viral load – less than 48 copies/ml
• length of time HIV positive – between 20 and 30 years

Results

Researchers released data on six of the volunteers. In general, CD4+ counts increased by 100 to 300 cells above their starting levels. The sixth participant did not have a large increase, perhaps because his immune system was weakened or because it sensed that the modified CD4+ cells were somewhat different than normal and may have attacked them.

In five of the six men, between 6% and 7% of the modified CD4+ cells persisted for many months in the blood and lymph tissues in the gut. Some participants continued to have detectable modified cells for more than a year. Sangamo is continuing to fund studies to monitor these participants and is conducting other studies to explore the effects of gene therapy in HIV-positive people.

Reference:

Lalezari J, Mitsuyasu R, Deeks S, et al. Successful and persistent engraftment of Zfn-m-R5-d autologous CD4+ T cells (SB-728-T) in aviremic HIV-infected subjects on HAART. In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections, Boston, February 27–March 2, 2011. Abstract 46.