January 29, 2013
A new gene therapy could make a person's CD4+ cells resistant to HIV -- a method that, if successful, would eliminate the need for antiretroviral drugs for those living with HIV, according to a new study conducted by researchers at the Stanford University School of Medicine.
HIV replicates by infecting a person's CD4+ cells, which the virus enters through the CCR5 receptor (or, in rare cases, the CXCR4 receptor) found on the CD4+ cell surface. Inactivating these receptors would block HIV from entering the cells.
The study, led by Matthew Porteus, M.D., an associate professor of pediatrics at Stanford, follows in the footsteps of Sangamo BioSciences' ongoing research using zinc finger nucleases to artificially disrupt the CCR5 receptor on the surface of CD4+ cells. Porteus and his team take that approach and go one step further.
They used the same nuclease to zero in on an undamaged section of the CCR5 receptor's DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as "stacking."
Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.
Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn't been achieved before by genome editing. To test the [CD4+] cells' protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the [CD4+] cells to HIV.
This testing was done in vitro, with the single- and double-gene modifications showing some protective immunity against HIV. However, the cells with triple-gene modifications were by far the most resistant, showing more than 1,200-fold protection against CCR5-tropic HIV and more than 1,700-fold protection against CXCR4-tropic HIV. The CD4+ cells that hadn't been modified were infected by HIV within 25 days.
Porteus views this as an important step forward in HIV gene therapy, but pointed out two potential drawbacks. The method is designed to disrupt the CCR5 and CXCR4 receptors, but it could possibly cause a break elsewhere in the genetic code, which could lead to cancer. Additionally, the cells may not accept the genetic modifications at all. However, Porteus believes both problems are technically surmountable.
While this method could eventually become a therapeutic vaccine for those already living with HIV, Porteus is unsure about its value as a preventative vaccine. "I think of vaccines as treatments that activate the immune system to eradicate the virus upon initial infection," he told TheBodyPRO.com. "Theoretically, one could use this treatment in high-risk individuals to give their immune system an HIV-resistant component. You would not want to do that in uninfected individuals until the process had been shown to be extremely safe in infected patients."
As to how he would apply this method in human patients, Porteus explained: "I think there are methods whereby you could modify a large number of CD4+ cells (maybe up to a billion). But that seems like a daunting task. An alternative approach would be to modify the blood/lymphocyte stem cells that give rise to CD4+ cells. Since each stem cell has the potential to give rise to many, many CD4+ cells, if you could modify the stem cell, then all of the progeny of that stem cell would be resistant. So I think modifying CD4+ cells is the shorter-term target, but modifying the blood/lymphocyte stem cells has the potential to be a more robust approach."
The researchers' next step will be testing the strategy in CD4+ cell samples taken from HIV-infected patients, and then moving onto animal testing, with the hopes of starting human clinical trials in three to five years.
The study was published in the Jan. 22 issue of Molecular Therapy, according to the Stanford release.
Warren Tong is the research editor for TheBody.com and TheBodyPRO.com.
Follow Warren on Twitter: @WarrenAtTheBody.
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