A Cellular Compass for HIV?
By Rowena Johnston, Ph.D.
May 18, 2006 - HIV is a remarkable virus, given the considerable hurdles it must overcome to successfully complete its life cycle. Even after side-stepping the heroic, but ultimately unsuccessful, efforts mounted by the immune system to eliminate it, HIV must navigate a complicated series of steps before it can reproduce itself inside human cells.
Dr. Mario Stevenson, chair of amfAR’s Scientific Advisory Committee and Research Committee of the Program Board, has recently described how HIV co-opts human proteins to complete one of the final steps needed before it can start reproducing itself. The findings, published in the prestigious journal Nature, may help scientists discover new ways to combat the virus.
“Each new finding in the HIV/AIDS field reveals an astonishing level of complexity to this virus that helps us understand why it is so difficult to conquer,” said Dr. Stevenson. “But each time we discover a new way in which HIV critically relies on certain human proteins, it gives us hope that we can use this information to devise new strategies to treat and maybe even eliminate HIV one day.”
This new hope rests on a fundamental property of HIV. Like all viruses, HIV infects its host armed with a bare minimum of tools—it consists of only nine genes and 15 proteins. Viruses, including HIV, make up for this shortfall by enlisting proteins normally found in their hosts, bending them to their own purposes.
Unlike most other viruses that infect humans, though, HIV must complete an additional step in order to begin replicating. It must insert, or integrate, its own genes into the genetic material of each human cell it infects. To do so requires crossing the membrane that separates the main body of the cell from the nucleus, where human DNA resides. Once inside the nucleus, HIV must find a suitable stretch of DNA to settle into.
Dr. Stevenson and his colleague Dr. Jean-Marc Jacque have discovered that a protein called emerin plays a critical role in helping HIV find the genetic material of the cell it has infected. Emerin, a human protein embedded in the nuclear membrane, connects the membrane to the genetic material inside. Drs. Stevenson and Jacque worked with macrophages, a type of immune cell that forms one of the main targets of HIV infection. They in effect removed emerin from the cells using siRNA, a sophisticated tool that can “silence” specific genes. When emerin was no longer active in the macrophages, HIV found its way to the nucleus but did not appropriately integrate into the genetic material inside—in essence the virus failed to establish itself in the cell.
A series of subsequent experiments examined the mechanisms by which HIV is blocked when emerin is absent. They concluded that emerin and another human protein, BAF (barrier-to-autointegration factor) work cooperatively to guide HIV to a suitable region of DNA. When their activity is blocked, HIV is unable to appropriately situate itself and becomes more susceptible to normal degradation processes inside the nucleus.
Drs Stevenson and Jacques concluded that this interaction between HIV, emerin and BAF constitutes a promising new target for the development of anti-HIV drugs. Such drugs could potentially “promote abortive HIV-1 infection of a cell,” they wrote. This would be a promising goal indeed.
Dr. Johnston is director of research at amfAR.