The Hunt for Hidden HIV Has a New Weapon

A research team at the Salk Institute has uncovered a crucial and previously unknown mechanism used in the cellular replication process of HIV. The key to rooting out dormant (and undetectable) HIV may lie in a single unassuming enzyme—one of many involved in the HIV replication process, but one whose absence may prevent the virus from spreading its genetic material and, thus, itself.

The challenge of HIV is in its ability to hide and wait. The virus is patient, seeming to disappear within the body when threatened, yet always managing to maintain some foothold from which it might regenerate. HIV is the guerrilla army of infectious disease.

The virus can lay dormant for years in the human body, living within (or as part of) the immune system's CD4+ T cells. These are the cells that mediate the body's responses to toxic or otherwise bad stuff, e.g. foreign antigens. Knocking them out wrecks the immune system's ability to detect pathogenic invaders, which is how AIDS kills.

T cells can be long-lived, acting as an immune system memory of sorts. If you were some virus in need of a hiding place (from antiviral drugs or the immune system itself), T cells are a convenient solution. When the virus is dormant, it's no longer producing any actual HIV particles. Instead it just hangs out, safely hidden within its immune cell host in a more or less undetectable state.

The key to curing HIV/AIDS is in the ability to root out this sort of latent infection. Basically, we need to make the virus begin reproducing itself. As such, it will have given away its position and can be targeted, by the immune system's own defenses and by potential new therapies. The highly-active antiretroviral drugs we use on HIV now are really, really good at killing HIV—and have saved many millions of lives—but they can only kill HIV if they see HIV. Current treatments are always almost but never quite finishing the job.

The new research, which is detailed in the current issue of the journal Genes & Development, describes a new protein thought to be responsible for "waking up" dormant HIV cells. The protein, known as Ssu72, interacts with an already well-known protein called tat, for "trans-activator of transcription." Tat's job is to act as a chemical lookout for the virus, signalling when conditions are favorable for replication.

When activated, the tat acts as a helper molecule in the process of DNA replication. When HIV or any other virus gets ready to move out, it starts making more of itself. To do so, viruses find host cells, into which they inject their genetic material, turning the host into an unwilling or unwitting virus factory. The flu, for example, plants itself within the cells lining the respiratory tract, while rabies starts off within muscle tissue and eventually moves on to the brain. The virus behind polio, poliomyelitis, uses nerve cells as hosts. HIV, of course, goes after immune cells. As a catalyst, tat gives HIV cells the go- ahead to replicate within these cells.

To get to the root of tat, the Salk researchers compiled a list of 50 or so other proteins that the protein interacts with. One stood out: Ssu72.

Ssu72 is an enzyme (most enzymes are proteins) that had been shown in previous research to catalyze genetic transcription within yeast cells. The researchers decided it merited a closer look. What they found is a potential gateway to an HIV cure.

Ssu72 acts by binding itself chemically to the tat protein. This binding is not only helpful but necessary for tat to do its own job. So: Ssu72 is not only helpful but necessary for HIV to begin replicating. That's huge.

"Tat is like an engine for HIV replication and Ssu72 revs up the engine," said Lirong Zhang, one of the first authors and a Salk researcher, in a statement. "If we target this interaction between Ssu72 and Tat, we may be able to stop the replication of HIV."

HIV researchers had previously identified something a whole lot like Ssu72, an enzyme called CycT1. The catch with CycT1, however, is that it's needed for normal, healthy cell functioning. Killing it off then means a whole lot of collateral damage.

"Many proteins that Tat interacts with are essential for normal cellular transcription so those can't be targeted unless you want to kill normal cells," said the study's co-first author, Yupeng Chen. "Ssu72 seems to be different, at least in the way it is used by HIV."

There are two rather different-seeming directions the team (and the research) goes from here. One is intuitive: how to target and inhibit the Ssu72. The other is more subtle. It's possible that lower levels of the enzyme are responsible or partly responsible for the virus's dormancy. Ssu72 then might be useful for waking HIV up so that it can be targeted.

As an HIV wake-up call, this wouldn't be the first of its kind. In 2012, researchers completed testing of a compound known as SAHA on human subjects. SAHA also acts to induce HIV replication and, what's more, it appears to be safe in humans. That's a big deal, but as the SAHA researchers noted then, an HIV cure has two distinct sides, the wake-up call and the actual eradication. We're at least half-way there.