In some ways, HIV resembles a minimalist painter, using a few basic components to achieve dramatic effects.
The virus contains just nine genes encoding 15 proteins, which wreak havoc on the human immune system. But this bare bones approach could have a fatal flaw. Lacking robust machinery, HIV hijacks human proteins to propagate, and these might represent powerful therapeutic targets.
Using a technique called RNA interference to screen thousands of genes, Harvard Medical School researchers have now identified 273 human proteins required for HIV propagation. The vast majority had not been connected to the virus by previous studies. The work appears online in Science Express on Jan. 10.
Drugs currently used to treat the viral infection interact directly with the virus itself, and it's quite simple for the rapidly mutating virus to avoid destruction by altering how it interacts with these chemicals. Patients use a cocktail of HIV inhibitors because the virus is less likely to evolve resistance to multiple drugs at the same time. But some HIV strains have still managed to evade particular drugs. These could eventually develop resistance to several drugs, especially among patients who don't adhere to their regimens.
“Antiviral drugs are currently doing a good job of keeping people alive, but these therapeutics all suffer from the same problem, which is that you can get resistance, so we decided to take a different approach centered on the human proteins exploited by the virus,” says Harvard Medical School (HMS) Professor and senior author Stephen Elledge, who holds primary appointments in the Department of Genetics and at Brigham and Women's Hospital. “The virus would not be able to mutate to overcome drugs that interact with these proteins.”
Labs around the world have made impressive contributions to our understanding of the HIV life cycle. Over the last two decades, they've identified dozens of human proteins, or host factors, required for HIV propagation. The new study builds on this work, essentially quadrupling the list of host factors to include proteins involved with a surprising array of cellular functions ranging from protein trafficking to a type of programmed cell death called autophagy.
“The expanded list is a hypothesis generation machine,” explains Elledge, who is also a member of the HMS-Partners Health Care Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute. “Scientists can look at the list, predict why HIV needs a particular protein, and then test their hypothesis.” He hopes that such research will lead to new therapeutics.