The researchers have discovered a specific genetic trigger that makes HIV hibernate but awaiting an opportunity to re-emerge.
They studied an HIV protein called Tat, which plays a major part in initiating and also interrupting the cascade of chemical reactions that leads to full-blown infection. They have proposed that the Tat protein and the enzymes that modify it serve as a “resistor,” a component of an electrical circuit that reduces the flow of current.
HIV weakens the body’s immune system by invading CD4+ T cells and killing the cells in the process, which help defend the body against illness. Without these T cells the body loses its ability to repel other infections.
On rare occasions, however, a virus will infect the T cell and become dormant. The scientists found the answer to this in a strand of HIV’s DNA where a genetic circuit exists and in the Tat protein.
An important player in the genetic circuit is an enzyme within the T cell called p300 that decorates the Tat protein with a small chemical tail. The p300 enzyme converts the Tat protein into a message that activates the virus and creates more Tat protein, and eventually converts the T cell into an active HIV factory.
Mechanisms do exist to halt the process, however. For example, another enzyme within the affected cell called SirT1 is capable of pulling the chemical tail off the Tat protein, rendering it silent. The interplay between p300 and SirT1 comprises the resistor and can effectively keep the virus in its dormant phase.
“If we can create drugs that target these enzymes, perhaps we can get SirT1 and related enzymes to assert themselves immediately, forcing HIV into hibernation with high frequency and reducing the threat to the host,” said Princeton scientist Leor Weinberger.
Drugs already exist that target other cellular enzymes, so the researchers hope the discovery will stimulate more research into potential gene-targeted therapies.