Tat and a potential off-switch for HIV

A Princeton University study suggests it may be possible to deactivate viruses such as HIV 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," Shenk said. "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 reported their findings in the December 26 issue of the online journal Public Library of Science Biology.

Though Weinberger emphasised 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," he 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 defence 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.

On rare occasions, however, a virus will infect the T cell and become dormant. Why this individual viral infection would not begin to replicate when others do remains a mystery.

"It's somewhat like the unpopped kernels of corn left in the bottom of the bag when you take it out of the microwave," Weinberger said. "They were exposed to the same heat as the others but did not pop. We wanted to know why about one in a million HIV particles didn't 'pop' immediately like all the rest did."

Weinberger and Shenk found the answer in a strand of HIV's DNA. First, one of HIV's genes creates the Tat protein, which is part of the chemical signal for the virus to begin replicating. An important player to complete the signal 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.

"The more of these [messages] sensed within the cell, the more Tat proteins the gene creates, resulting in a snowball effect that is difficult to stop," Weinberger said.

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.

"SirT1 reduces the strength of the signal to replicate," Weinberger said. "It may prove to be the key part of the resistor in the circuit, as our mathematical models are strongly suggesting."

Source: Princeton University