Scientists find potential 'off-switch' for HIV virus

While there is no cure for lingering viral infections such as HIV and herpes, a recent study at Princeton University suggests it may be possible to deactivate such viruses indefinitely with the flick of a genetic switch.

Princeton scientists Leor Weinberger and Thomas Shenk hope their work will illuminate the processes by which human immunodeficiency virus (HIV) and other viruses transition into dormant phases in their hosts. The researchers have discovered a specific genetic trigger that makes HIV fall into its latent phase, where the virus essentially hibernates, relatively harmlessly, but awaiting an opportunity to re-emerge and wreak havoc.

Weinberger and Shenk studied how an HIV protein, called Tat, plays a major part in initiating and also interrupting the cascade of chemical reactions that leads to full-blown infection. Based on their work and previous studies by others, 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.

"The resistor paradigm is a helpful way to think about how HIV enters and exits latency, and it might serve as a useful model for latent infections by other viruses, as well," said Shenk, Princeton's James A. Elkins Jr. Professor in the Life Sciences in the Department of Molecular Biology. "Understanding how to activate the Tat resistor to interrupt the reactions leading to viral infection could one day have repercussions in both the lab and the clinic."

Weinberger and Shenk share their findings in a research paper appearing in the Dec. 26 issue of the online journal Public Library of Science Biology.

"We have helped understand how HIV can turn off, and in doing so I believe we've uncovered an important component of the biological switch," said Weinberger, a Lewis-Thomas Fellow in Princeton's Department of Molecular Biology. "If we can figure out how such resistors affect viruses, it might lead to a whole new class of drugs that can treat some of the world's most dangerous illnesses."

Though Weinberger emphasized the significance of the discovery was primarily for fundamental science research, he said that potential applications to HIV might be an improvement over drug cocktails, which are the mixtures of antiviral agents that have been the best-available treatment for the disease for a decade.

"Drug cocktails extend the life of the patient, but they do not completely alleviate the symptoms of HIV, nor do they work for all victims," Weinberger said. "Even when the cocktails get most of the infectious virus in a victim's body, some viruses will escape because they have hidden by going dormant. Eventually, these dormant viruses wake up and the infection returns, so it makes sense to try to keep the virus asleep if possible."

HIV weakens the body's immune system by invading CD4+ T cells, which in essence serve as the metaphorical generals in the body's defense system against illness. When an HIV virus particle invades a T cell, most often it converts the cell into a factory for making other viral particles, killing the cell in the process. Without these T cells, the body loses its ability to repel other infectious bacteria and viruses, and eventually dies from assaults from these other "opportunistic" infectious invaders.