HIV and the gut: Why it matters for a cure

When people think of HIV, they often picture it in the blood. But in reality, one of the most important places HIV hides is in the gut. The gut is not only for digestion—it is the body’s largest immune organ, containing a vast number of immune cells. Because of this, HIV quickly establishes itself there during infection and creates what scientists call a “reservoir”—a hidden store of virus that persists even when antiviral treatment keeps HIV levels undetectable in the blood.

Why the Gut Is So Vulnerable

The gut is packed with special immune cells, many of which HIV can easily infect. Early in infection, HIV destroys huge numbers of these cells, especially those needed to keep the gut barrier strong. When this barrier weakens, bacteria and fungi from the gut can leak into the bloodstream, causing chronic inflammation. This constant immune activation makes it easier for HIV to persist, creating a cycle that antiviral treatment alone cannot break.

The Limits of Current HIV Treatment

Modern HIV therapy is very effective at controlling HIV in the blood, but it does not clear the virus from hidden reservoirs. One reason is that antiviral therapy does not always reach high enough levels in gut tissues. Even long-acting injections, which work well in blood, sometimes fail to fully suppress HIV activity in the gut. This is why people on treatment can still show signs of inflammation and immune dysfunction linked to gut damage.

Emerging Strategies to Tackle HIV in the Gut

Scientists are looking at different strategies to try and cure HIV, and for each of these strategies the gut needs to be considered.

1. Latency reversal agents (LRAs): These drugs aim to “wake up” sleeping HIV so the immune system can see and destroy infected cells. However, the gut’s unique environment makes this harder than in blood, so gut-specific strategies may be needed.
2. Immune-boosting therapies: These include drugs that restore tired (“exhausted”) immune cells, special antibodies that guide immune cells to infected sites, and new biologic therapies that strengthen antiviral defences in gut tissues.
3. Broadly neutralising antibodies (bNAbs): These powerful antibodies can both block HIV infection and help immune cells kill infected cells. Delivering them directly to mucosal tissues (like the gut or vagina) may increase their effectiveness.
4. Restoring gut health: Since inflammation and microbial imbalance play such a big role, researchers are testing probiotics, faecal microbiota transplants, anti-inflammatory drugs, and therapies to repair the gut barrier.
5. Therapeutic vaccines: Unlike vaccines designed to prevent infection, these aim to retrain the immune system of people living with HIV to better control the virus, especially in gut tissues.
6. Gene and cell therapies: Cutting-edge approaches like CRISPR gene editing and engineered immune cells (CAR-T cells) may eventually allow scientists to remove HIV DNA from gut cells or replace vulnerable cells with resistant ones.
7. Targeted delivery systems: Researchers are designing nanoparticles and antibody-drug conjugates to carry treatments directly to infected gut cells, improving drug penetration while reducing side effects.

Looking Ahead

The gut represents one of the biggest challenges to curing HIV. It contains most of the body’s immune cells, making it a large and complicated hiding place for the virus. Scientists now believe that a combination approach—one that repairs gut damage, boosts immunity, reverses latency, and delivers therapies directly into gut tissues—will be needed to achieve long-term remission or even a cure.

In short, curing HIV isn’t just about clearing the virus from the blood. The gut, with its unique structure and immune role, is central to the problem—and also to the solution.

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