Gene therapy forces HIV to enter permanent sleep

Scientists at Johns Hopkins Medicine have discovered a way toward HIV’s own genetic mechanisms, potentially providing lasting treatments for the virus that causes HIV.

By amplifying naturally occurring molecules that HIV produces its own activity, the researchers successfully forced the virus to stay dormant in human immune cells for a long time, a state in which HIV cannot replicate or cause disease.

This approach represents a fundamentally different strategy from current HIV treatments, which requires daily medication to inhibit viral replication. Rather than fighting the virus with external drugs, the gene therapy uses HIV’s own regulatory mechanism to lock it into a permanent sleep.

Built-in sleep switch for HIV

The key is to understand how HIV naturally controls its own activities. Like many viruses, HIV produces an “antisense transcript” called AST, which is actually a molecular switch that can put the virus to sleep when conditions are not conducive to replication.

“Our aim is to find a way to provide a lasting, lasting treatment for HIV,” explains Dr. Rui Li, a postdoctoral fellow at the Johns Hopkins Laboratory, which conducted the study and published the first author of the study in scientific advances.

The research team is led by Fabio Romerio, PhD, associate professor of molecular and comparative pathology at the Johns Hopkins School of Medicine, and genetically designed immune cells can produce large amounts of AST. The result is dramatic: HIV transcription (the process by which the virus uses to make its own copy) drops to almost undetectable levels.

Tested in real patient cells

The most compelling evidence comes from experiments using CD4+ T cells collected from 15 people receiving standard antiretroviral therapy. The virus was still asleep when the researchers introduced the DNA that produced AST into these cells and then tried to awaken dormant HIV with a powerful stimulant.

The main findings of the study:

• AST prevents HIV reactivation in cells of all 15 HIV-positive participants
• The silence effect lasted for four days until the introduced DNA degradation
• Various HIV activation methods fail to restart virus replication
• No adverse reactions were observed in treated cells

Experiments show that AST works by recruiting a complex network of cellular proteins that modify the structure of DNA around the HIV genome, effectively sealing it in an inactive state. The molecule concentrates these inhibitory factors on viral DNA, creating what researchers call a “blocked chromatin state” that prevents transcription.

From discovery to treatment

This study is based on an increasing understanding of how HIV establishes and maintains latency – when the virus is dormant in infected cells. Current HIV drugs can lower virus levels to undetectable amounts, but they won’t eliminate the underlying virus, which may recover if treatment stops.

AST represents what scientists call “first-class biomolecules” that can perform HIV latency. Unlike traditional drug approaches targeting specific viral proteins, this strategy manipulates the entire regulatory network that controls viral gene expression.

The structure of the molecule contains specific domains with different functions: one region directly binds to HIV’s DNA, while the other region recruits the cellular mechanisms that silence gene expression. Through detailed mapping studies, the researchers identified the precise sequence motifs required for AST activities, and this knowledge could guide more efficient versions of engineering.

Looking for clinical applications

For future therapeutic applications, researchers envision AST by performing AST with gene therapy vectors that have been approved for other diseases. This method will require stable, long-term expression of AST in infected cells to maintain viral inhibition.

“This provides the rationale for testing AST as a therapeutic agent that can limit HIV-1 transcription and stabilize the viral latency,” the researchers wrote in their study.

This work addresses the key gap in HIV treatment research. Although much of the focus is on strategies to eliminate potential HIV reservoirs, fewer approaches explore permanent viral silencing. An estimated 1.2 million Americans with HIV-related illnesses are estimated to have an estimated 630,000 deaths a year, and any advance towards functional treatments has great significance.

The next steps involve optimizing the safety of AST for therapeutic use and testing animal models. If successful, this approach could transform HIV from a chronic disease requiring lifelong medication to a permanently silent infection, which actually turns the virus’s own regulatory mechanism into an inescapable molecular prison.

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