A drug used to treat parasitic infections in developing countries may play a valuable role fighting HIV alongside standard antiretrovirals, according to new research published January 31 in the online scientific journal Retrovirology.
Scientists have long known that HIV can safely sequester itself in certain types of white blood cells, enabling the virus to hide from the immune system and to evade the activity of antiretroviral medications. In turn, once antiretroviral therapy is stopped—even after several years of maintaining an undetectable viral load—HIV is released from its cellular sanctuaries, quickly repopulates the body with virus and continues its assault on the immune system.
Macrophages are one type of white blood cell that can be used by the virus as a sanctuary. Normally, macrophages circulate throughout the body looking for foreign microorganisms. If these cells are infected with a virus or stop functioning properly, they are supposed to undergo a process called apoptosis—cellular suicide. When macrophages are infected with HIV, however, they fail to undergo apoptosis and end up providing the virus with protection, well beyond their normal lifespan.
The new research from Baek Kim, PhD, associate professor at the University of Rochester Medical Center, and his colleagues may explain HIV’s troublesome life-extending effect on macrophages. According to Dr. Kim’s group, HIV turns on a series of cell survival signals—called the PI3K/Akt kinase pathway—that prevents apoptosis and extends the macrophage’s lifespan. The virus does this by inhibiting a molecule called PTEN, which is responsible for disrupting the PI3K/Akt signal when something goes wrong with the cell.
Miltefosine (Impavido), used in South America and Asia to treat leishmaniasis, a potentially fatal parasitic disease, is a known inhibitor of the PI3K/Akt pathway. In fact, it was originally studied as a chemotherapeutic agent, in an effort to get cancer cells to commit suicide. Dr. Kim’s group confirmed that miltefosine inhibited the PI3K/Akt pathway in HIV-infected macrophages, thus countering the effects of the virus on PTEN.
“Miltefosine puts an end to the long lives of HIV-infected macrophages,” Dr. Kim says. “The fact that it is already used in humans could accelerate the process of seeking government approval for a new, anti-HIV use for miltefosine, or something like it. In the next phase, we will conduct studies seeking to show that Akt inhibition ends the survival of HIV-infected macrophage reservoirs under real-life conditions.”
Research evaluating strategies to flush HIV from “memory” CD4 cells, the second type of white blood cell that can harbor HIV for years or decades, has been under way since the late 1990s.