November 3, 2012
How close are we to an HIV cure? What have we learned from the precious few "functional cure" cases out there, and what other interventions are being developed?
To answer these questions, Joseph Eron, M.D., director of the University of North Carolina Center for AIDS Research, provided an overview of HIV cure research at IDWeek 2012. In his presentation, he reviewed the barriers to a cure, while highlighting the current and potential strategies being researched.
Eron started by highlighting the known cases of patients who appear to have been "functionally" cured of their HIV infection. Timothy Brown, whose case has been widely reported, received two stem-cell transplants for leukemia in 2006. His CD4+ cells were replaced by the donor's CD4+ cells, which lacked the CCR5 receptor that HIV primarily attaches to, effectively making him immune to most forms of HIV. He has been off therapy for over five years without the virus rebounding.
Similarly, two other patients show no traces of HIV in their blood after receiving stem-cell transplants. Unlike Timothy Brown, these two patients received donor cells that did not lack the CCR5 receptor. However, because they were on antiretroviral therapy during the transplant period, the donor cells were not infected with HIV. Although the two patients are still on treatment, at 1,300 days post-transplant, no virus can be detected, even with a single-copy assay.
Eron noted that stem-cell transplants are too toxic, too dangerous and too expensive for most individuals living with HIV. However, he suggested that for HIV-infected individuals who need a stem-cell transplant, curing HIV should also be a goal. Regardless, he said, any intervention should be time limited and tolerable, with only moderate risk and a measurable level of success -- it doesn't have to be 100%, Eron said, but we have to start somewhere.
The first and biggest hurdle to achieving a cure for HIV is an infected person's pool of latently infected cells, specifically resting CD4+ cells, Eron pointed out. These cells would be part of hidden HIV "reservoirs" that continue to evade current antiretrovirals. There are different reservoir sites in the body, including the blood, gut, central nervous system and kidneys. They consist of resting CD4+ cells, but could include other cell types. Targeting and eradicating the HIV reservoir remains the number one challenge, Eron said.
Eron also briefly mentioned the role that may be played by long-lived cells, such as macrophages and microglia. "Turns out if you get chemotherapy and radiation, your microglia in your brain actually turn over. That's perhaps one reason why people who get transplants don't relapse in the brain with HIV," he stated. While residual HIV replication may exist in the body, Eron hypothesized that it probably exists in a low level and wouldn't be a major barrier to a cure.
The last barriers Eron listed were HIV-specific immunity loss and generalized immune dysfunction among patients who have been virally suppressed for a long time.
After patients start treatment, HIV doesn't seem to evolve or diversify for at least six years among those who stay on treatment, Eron said, referencing work done by Mary Kearney, Ph.D., and John Coffin, Ph.D. However, Eron raised a finding he found particularly disturbing: HIV "clone cells" that were showing up five or six years after treatment initiation. "There are things called predominant plasma clones. This is a clone of the virus that's almost identical. There are some cells that are producing identical virus over long periods of time," Eron explained.
"That either means there's one cell producing a giant amount of virus that lives for a long time, or what I think is going on: There's probably a cell that's divided -- maybe it was a stem cell and then it proliferated -- and it continues to produce virus. I think those may be another hurdle we may run into," he continued.
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