Waking HIV from its secret hiding places

Why our ARVs can’t reach HIV in hiding

For people living with HIV, modern antiretrovirals (ARVs) can suppress the virus to undetectable levels and allow people to live long, healthy lives, but ARVs don’t get rid of it.

What scientists call the HIV reservoir is central to this challenge.

Paula explains: “The reservoir is essentially the HIV that is still hiding in your body even when antiretroviral therapy has suppressed the virus to undetectable levels. Treatment is doing exactly what it should—keeping people healthy and preventing transmission—but there are parts of HIV that are still present.”

It hides by inserting itself into the DNA of certain immune cells, forming a reservoir the body can’t detect. This is why, if treatment stops, the virus rebounds—often within weeks. Some of these cells hiding HIV are extremely long-lived, surviving for years or even decades.

“As soon as you stop taking your treatment, this hidden HIV can come back,” Paula explains. “And that is why people with HIV have to take medication lifelong.”

For decades, scientists around the world have been trying to find a safe way to eliminate this hidden virus or HIV Reservoir. A true cure would mean removing the reservoir entirely—so people could stop treatment without the virus returning.

The mRNA breakthrough

Many people first heard about mRNA during the COVID-19 pandemic, but it’s something our bodies use constantly. This new approach using mRNA will deliver a powerful protein that targets HIV directly inside cells.

Paula explains that mRNA is really a messenger molecule. ‘It passes on different instructions within our cells—what to do every minute of every day.”

Crucially, mRNA is temporary. It’s almost like a single-use message. Once the instructions are delivered, the message disappears. It doesn’t change your DNA and doesn’t make any other permanent changes to your cells. It just tells the cell: ‘Today, I would like you to do this’. And in this case, the mRNA carries instructions to produce Tat, an HIV protein that acts like an “alarm bell” waking up HIV, so it can be seen.

Latency reversal or ‘waking up the virus’

In science terms, the strategy is known as latency reversal, or more simply: waking up the virus.

Researchers package the mRNA inside ‘lipid nanoparticles’ – or tiny fat bubbles – to protect it, because mRNA is very fragile and needs to be kept intact to reach those cells where HIV is hiding in deep slumber. Wrapped in a layer of fat, this allows the mRNA to avoid destruction by enzymes or the immune system along the way.

This is the latency reversal step. But the next step is just as critical: destroying those newly visible cells with active HIV. When the sleeping HIV turns back on and begins making more copies of itself, it has revealed itself to the immune system.

“Generally, the body is able to kill HIV,” Paula says. “But it’s just not good enough to do this when the virus is multiplying very quickly.” In other words, it needs a little help.

This is why ARVs are so important. ARVs will stop the awakened virus from spreading by slowing its multiplication – giving our immune system a chance to safely clear the cells that contain HIV.

“In a clinical trial, if we get this far, we therefore want people to continue taking their HIV treatment,” Paula explains. “This protects healthy cells and allows the immune system to do its job. And over time, the hope is that repeated cycles will shrink the reservoir—potentially to zero.”