One of the main reasons we don’t yet have a cure for HIV is that the virus goes into a “sleep mode” and hides its genetic material inside some of our immune cells. Even though treatment can stop HIV from replicating and prevent disease progression, these hidden cells – called the latent reservoir – remain under the radar, ready to rebound once medication is stopped.
Researchers are working hard to find ways to not only suppress HIV, but to help people live without daily medicine and prevent the virus from ever rebounding if treatment is stopped.
What is latency reversal and how is it achieved?
Latency-reversal agents are drugs designed to wake up sleeping virus. Once the virus starts replicating again, infected cells become visible to the immune system to be targeted for clearance or so other treatments can clear them. This strategy is often called “shock and kill”: first, shock the virus awake using latency reversal agents, then kill or clear the infected cells.
What does the current research tell us?
- The cells that make up the latent HIV reservoir are long-lived, hidden, and not actively producing virus, so they don’t trigger immune responses.
- Scientists are testing many different types of latency reversal agents, including some drugs originally developed for cancer. Some have been shown to wake up latent HIV, both in the lab (on cells donated by people with HIV) and in clinical trials in humans. It is important to note that when cancer drugs are used in HIV latency reversal studies, they are administered in much smaller doses than those given to people undergoing cancer treatment.
- Importantly, latency reversal alone is not enough. Waking up the virus doesn’t guarantee that the infected cell will be cleared. that boost the immune system or assist the “kill” part of the strategy.
- There are risks and challenges: and we must ensure healthy cells aren’t harmed. Finding a cure for HIV that is safe, scalable, and effective in the people who need it most, remains a work in progress.
Why does this matter for people and communities?
- A cure for HIV could mean living without daily medication, fewer side-effects and long-term health issues, and facing less stigma and discrimination that many people with HIV experience.
- The latent reservoir is the barrier that keeps us from achieving this goal, meaning that this work is central to the hope of achieving a cure for HIV.
- Having accessible, safe, and affordable cure strategies matters, especially for communities around the world where long-term treatment, side-effects, or access remain big challenges.
History of latency reversal agents:
There are many types of latency reversal agents and each class works differently to reactivate the latent virus. Some control the expression of genetic material, some activate signalling pathways in cells, and some stimulate immune responses. Laboratory experiments using cells donated by people with HIV as well as animal studies (often mice or monkeys), have shown many latency reversal agents to be effective at reactivating virus. However, as a cure strategy they haven’t yet been proven effective in human clinical trials.
Multiple clinical trials with latency reversal agents took place in the 2010s. Vorinostat (a drug designed to increase genetic material expression), bryostatin (increases cellular pathway signalling) and Lefitolimod (an immune booster) started to reactivate virus in people with HIV who were taking antiretroviral therapy but did not fully complete the process. The virus needs to be completely reactivated for the immune system to detect and eliminate the infected cells.
Clinical trials with these traditional latency reversal agents showed that they are not strong enough at reactivation. In addition, these treatments affect all cells in the body and don’t just target the latent HIV reservoir. Therefore, there are concerns with toxicity caused by traditional latency reversal agents.
Tackling issues in shock and kill:
Thanks to ongoing research, we now have a better understanding of the latent HIV reservoir. Cells with latent virus are not getting killed and cleared because they have a defence mechanism to survive and persist. In light of this, researchers began to look at ways to interfere with this survival mechanism. SMAC mimetics and venetoclax are examples of such drugs that prevent the cells from surviving and help the immune system more easily clear out the infected cells. However, these drugs are also not specific to cells with latent virus, meaning they can affect healthy cells and cause unwanted side effects.
- There are many types of SMAC mimetics and some have been tested in clinical trials as drugs for treating cancer. AZD5582, belonging to the family of SMAC mimetics but yet to be tested in people, showed strong latency reversal effects in monkeys, however it did not reduce the size of the HIV reservoir.
- Venetoclax is a drug that is used to treat cancer and when tested in the laboratory in cells and animals, killed latently infected cells and reduced the size of the HIV reservoir. There is a clinical trial called the AMBER study happening at the moment in Denmark and Australia to assess the safety of this drug in healthy people with HIV.
The other arm of the approach requires our own immune system. We need strong anti-HIV immune responses so that the reactivated cells can be effectively eliminated from our body. However, the immune system in people with HIV is not in its optimal condition and is rather “exhausted”. To address this issue, the immune boosting drugs are designed to strengthen and improve the immune response. Some immune boosters can also act as latency reversing agents.
- Pomalidomide is an immune enhancing drug and the clinical trial to test its safety is happening in Denmark and Australia (the ).
- Nivolumab is a drug that reverses immune exhaustion and is used to treat some cancers. There is an ongoing clinical study in Australia (NIVO-LD) to test its effect in people with HIV.
- Broadly neutralising antibodies, or bNAbs, recognise and block many strains of HIV from entering healthy cells and tag them so other immune cells can help to clear infected cells
New generation of latency reversal agents:
Researchers are now working on the new generation of latency reversal agents that may be able to overcome many of the existing issues. One example of that is “Tat LNP”. It is designed to target HIV infected cells only, and was shown in the lab to be very effective at reactivating cells that had been donated by people with HIV (https://thorneharbour.org/news-events/news/covid-19-vaccine-tech-brings-us-a-step-closer-to-an-hiv-cure/). By being very potent and specific, it should address the issue with toxicity. This research is still in its early stages. The team are now testing it in animals, and hope to move it into clinical trials in the near future.
So, what does reactivating the virus mean for people participating in latency reversal trials? In the era of U=U, it is extremely important that we discuss this. Usually, participants stay on antiretroviral therapy while they receive latency reversal agents, therefore the pool of latently infected cells or the HIV reservoir will not increase. Also, the level of reactivation is expected to be very low, meaning that participants are very unlikely to be able to pass HIV on to their sexual partners. Viral levels are closely monitored by doctors during latency reversal clinical trial.
HIV has been playing a long game of hide and seek in the body, but research into latency reversal is helping scientists learn how to find and expose its last hiding places. While a complete cure isn’t here yet, progress is moving quickly, bringing real hope for a future where treatment is simpler, safer, and maybe no longer needed at all.
Key takeaways:
- HIV can hide in our cells in a ‘sleeping’ state that current treatments don’t eliminate.
- Latency reversal is one promising way to expose the hidden virus so it can be cleared.
- Traditional latency-reversal agents could partially reactivate HIV in laboratory cell studies and in clinical trials involving people with HIV, but are not powerful enough and not specific to cells with latent virus.
- There is a new generation of latency reversal agents that could tackle these issues.
- Latency reversal alone isn’t enough – we also need ways to clear the infected cells and support our immune system.
- While we’re not yet at a cure, the research is moving forward and offers hope for a future where treatment might be simpler, safer and more accessible.