Researchers Target and Awaken Dormant HIV in Groundbreaking Advance

When HIV infects immune cells (primarily CD4⁺ T cells), it behaves a bit like The Manchurian Candidate. If you’ve read the book or seen the movie, you know the plot: A soldier is secretly programmed to become an assassin, though his murderous nature is “asleep” until he encounters a specific trigger (the Queen of Diamonds) that prompts him to snap into action.

Much like The Manchurian Candidate, after integrating into a person’s DNA, HIV often enters a dormant state that allows it to evade both the immune system and antiretroviral therapy (ART). This is why ART can control the virus but cannot eliminate it.

Finding a way to wake up sleeping HIV and destroy the cells in which it hides before it can strike again is one of the main goals of HIV cure strategies. The problem, however, is that we’ve been missing a good Queen of Diamonds—something potent enough to reactivate latent virus, yet precise and safe enough to leave uninfected cells untouched.

Now a team of researchers at the Doherty Institute in Melbourne, Australia, with support from an amfAR Target grant, may have found just that. In a new study published in Nature Communications, they introduce specialized lipid nanoparticles (LNP X) capable of inserting mRNA, a piece of genetic material, directly into CD4⁺ T cells without harming uninfected cells.

These lipid nanoparticles, or “fat bubbles,” efficiently slip their mRNA cargo into CD4⁺ T cells that typically resist this kind of genetic delivery. In their LNP X, Prof. Sharon Lewin’s group encapsulated mRNA encoding a viral protein called Tat, which acts like a molecular alarm clock. Once inside the cell, it wakes up the dormant virus, making the infected cell visible to the immune system, which can then eliminate it.

As reported in the study, Tat delivered via LNP X reactivated latent HIV in CD4⁺ T cells from people living with HIV on ART, outperforming conventional latency-reversal strategies and without triggering immune activation and broad toxicity.

The team also used LNP X to deliver a CRISPR-based gene activator, a kind of programmable Queen of Diamonds, which could potentially be directed to push the virus out of hiding with great specificity. Even though the CRISPR approach was less potent than the Tat mRNA, it opens the door to even more targeted strategies in the future.

Of course, waking up the virus is just the first step. What the researchers are focusing on now is making sure that the reactivated cells are properly targeted and eliminated by the immune system.

While still at a preliminary stage of development, LNP X could transform the way we deliver mRNA to T cells, with implications for gene-editing therapies well beyond HIV.

If HIV is the sleeper agent, LNP X may just be the trump card we’ve been waiting for.

Dr. Gramatica is an amfAR vice president and director of research.

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