2024 HIV Cure Update: Breakthroughs, Challenges, and Future Research

August 26, 2024

Scientists have shared information about the “next Berlin Patient,” who appears to be the world’s seventh person cured of HIV following a stem cell transplant. Though the identity of the male patient is unknown, the moniker is a nod to the first patient, Timothy Ray Brown, who was cured of HIV and was known as the “Berlin Patient” before he publicly revealed his identity.

The “next Berlin Patient” had both leukemia and HIV and had received a stem cell transplant for leukemia in 2015. He had stopped taking antiretroviral treatment (ART) in 2018, and as of recently, tests show that he remains in HIV transmission.

The announcement of the seventh patient cured of HIV continues to hold promise that a cure may be found, and that the world may finally be able to end HIV as a global public health threat.

Does This Mean the Scientific Community Found an HIV Cure?

While the research shows tremendous promise since the first patient was cured in 2007 (made public in 2008), a viable cure is not yet available. Cases of HIV cures are rare, with only seven so far and still an estimated 39 million living with HIV as of 2023. However, there are also some cases where long-term control of HIV is happening without having to take treatment.

The continuing research holds promise, however, as significant progress has been made since HIV was identified over 40 years ago, and it is conceivable that a cure could be found sooner rather than later.

How Does HIV Work?

HIV is a master of disguise. It integrates its genetic material into the DNA of host cells, mainly the CD4 cells. These CD4 cells (white blood cells) are essential for coordinating the immune response. The virus then hijacks these cells, turning them into HIV factories that copy more of itself and gradually deplete the host body’s CD4 cells. This weakens the immune system and leaves the person vulnerable to infections and some cancers.

Why is Finding a Cure So Difficult?

While curing any disease is difficult due to a variety of factors, HIV has proven to be incredibly challenging for several reasons.

Viral Reservoirs: HIV can hide in various cells and tissues, creating a reservoir that remains unaffected by antiretroviral therapy (ART). The virus within these hidden reservoirs can reactivate at any time, making it difficult to eradicate the infection and making creating a vaccine or cure incredibly difficult.
High Mutation Rate: HIV mutates and evolves rapidly, which helps it evade the immune system and develop resistance to drugs.
Immune System Evasion: The virus targets and destroys the cells (CD4 white blood cells) that are supposed to fight it, stifling the immune response and making it even harder for the body to fight HIV. As more HIV is produced, fewer CD4 cells are created, making the person vulnerable to germs, diseases, and some cancers.

Innovative Strategies in the Search for an HIV Cure

Different HIV Cure Approaches

Scientists have been researching an HIV cure using a few different approaches.

Activate and eradicate – aims to flush the virus out of the reservoirs and kill any cell it infects – this is sometimes known as “shock and kill.”
Gene editing – this is about changing cells so that HIV cannot infect cells in the body
Immune modulation – this method permanently changes the immune system to better fight against HIV
Stem cell transplants – this approach replaces a person’s infected immune system with a donor immune system

Stem Cell Transplants

Stem cell transplants have been the most effective route to a cure so far. There have been seven successful cases with stem cell transplants, the first being the ‘Berlin Patient’ in 2007. While it is important to remember that researchers stress that each successful case is unusual and that attempts to replicate these treatments in other patients undergoing cancer treatment have failed, these cases provide a foundation that can be built upon to create a sustainable and less risky cure in the future.

Stem cell treatments have historically been used on cancer patients to treat that infection. This particular treatment uses a genetic mutation known as CCR5-delta 32 (discovered over 20 years ago), which hampers HIV’s ability to infiltrate immune cells. The CCR5 co-receptor is one that HIV uses to infect cells. Basically, the CCR5 co-receptor acts as a door that allows HIV entrance into the cell itself.

The mutation causes the CCR5 co-receptor outside the cells to develop smaller than usual and no longer sit outside the cell. Thus, the mutation, in a sense, “locks the door” and prevents HIV from entering the cell.

Research has found that this mutation appears in approximately 1% of the population, in people descended from Northern Europeans, particularly the Swedes, making those with the mutation immune to HIV infection. These people are homozygous carriers, meaning they inherited a copy from both parents. Estimates show that another 10-18% of people with European heritage have inherited a single copy of the gene. This single copy does not prevent infection, but it does reduce the carrier’s chance of infection and delays the progress of AIDS. To date, this gene mutation has not been found in Africans, Asians, or Amerindians.

By transplanting stem cells from a person with a homozygous (i.e. inherited from both parents) CCR5 delta 32 mutation, a team at Charité first successfully treated the Berlin Patient’s leukemia and fully eradicated HIV, the first successful case worldwide. Since this case, there have been six other cases using stem cell treatment, though some have varied in the type of transplant used.

It is rare that a person who is living with HIV also presents with the type of cancer that requires treatment using the stem cells of another person through transplantation. This type of stem cell transplant is incredibly complex and is associated with a mortality rate of approximately 10%, making it very risky, and thus, is only used in severe cases.

CRISPR Technology

In September 2021, the FDA approved the first human trial investigating using CRISPR gene-editing technology for an HIV cure. Excision BioTherapeutics conducted a trial and found that while EBT-101 (the name of the gene-editing therapy used) was safe and well-tolerated, it did not prevent viral rebound in three participants who stopped ART, according to an early study. However, it may have delayed viral rebound to 16 weeks after stopping ART in one participant, considerably longer than it typically takes.

Excision is now testing a higher dose of EBT-101 in a second cohort and continues to explore new CRISPR delivery methods that might be more efficient than the current method. One possibility is using lipid nanoparticles like the ones used to deliver messenger RNA in COVID-19 vaccines.

While the first cohort’s results were not as desired, its good safety profile suggests that a similar CRISPR approach may be feasible for other latent infections, such as herpes simplex (HSV) and hepatitis B (HBV). As HSV and HBV do not integrate their genetic blueprints into the chromosomes of host cells, these infections may be easier to remove using gene-editing technology, offering a possibility to cure these infections that also do not have a cure.

Patients Cured Using Stem Cell Transplants

The Berlin Patient

The first patient, Timothy Ray Brown, received a bone marrow transplant from a donor who was naturally resistant to HIV. Brown’s treatment involved destroying his bone marrow (which was producing the cancerous cells) and then receiving a bone marrow transplant. He had received this treatment for blood cancer (acute myeloid leukemia). The donor had double copies of a rare gene mutation known as CCR5-delta-32 that results in missing CCR5 co-receptors on T cells, the gateway most types of HIV use to infect cells.

While Brown was cured of HIV through his cancer treatment, the method was considered too risky and aggressive to be used routinely, though it does remain principally a cancer treatment.

The London Patient

The second patient cured of HIV, Adam Castillejo (known as the ‘London patient’), announced in 2019, also received a stem cell treatment from a donor with natural resistance to infection as part of treatment for Hodgkin lymphoma. Castillejo had stopped ART 16 months after the transplant, by which time, all his CD4 cells lacked CCR5 receptors.

The Dusseldorf Patient

Another patient, Marc Franke, known as the ‘Dusseldorf patient,’ received a stem cell transplant to also treat cancer (leukemia) from a donor who was also immune in 2013. However, Franke did not stop taking ART until 2018, and as such, his remission was not announced until 2019, though doctors did not declare him HIV-free until 2023 after more than four years of extensive testing.

The New York Patient

The first female case, the ‘New York Patient,’ had, as of February 2022, been off ART for 14 months without HIV returning. Her treatment was a different type of stem cell treatment, called a haplo-cord blood transplant (also to treat leukemia) and was done in 2017. This type of treatment is used when finding a close genetic match and using cells from more than one donor is difficult. In her case, umbilical cord blood from a donor with the double CCR5-delta-32 mutation was supplemented by cells from a relative without the CCR5 mutation. Significantly more people have the single mutation (heterozygous) than the double (homozygous) mutation, which is why this case is so important moving forward.

The City of Hope Patient

Paul Edmonds, a Californian dubbed the ‘The City of Hope patient,’ is the oldest to experience viral control without treatment. At 65, Edmonds has been living with HIV for 31 years and has the lowest CD4 nadir count (below 100). He stopped ART two years after his stem cell treatment (also to treat leukemia) and has shown no trace of HIV since, with his cancer also in remission.

The Geneva Patient

More recently, Romuald, a French-Swiss man, became the first person to experience HIV remission after a stem cell treatment that did not include the CCR5 mutation. He received a transplant after chemotherapy and radiation to treat leukemia. Host CD4 cells were completely replaced within a month of the transplant. Romuald got graft-versus-host disease, which occurs when donor immune cells attack the recipient’s body. This required further treatment with a JAK ½ inhibitor, which has also been shown to reduce the size of the HIV reservoir, and no viral rebound of HIV has occurred after 54 months post-transplantation.

This case is critical as it suggests that using stem cells with the CCR5 mutation may not be necessary to achieve long-term HIV remission, making it easier to find suitable donors for HIV-positive cancer patients who require a transplant. However, experts still advise caution is needed with further testing and monitoring.

The Next Berlin Patient

Most recently, a seventh person appears to be cured of HIV after receiving a stem cell transplant for cancer treatment. The case study was presented at AIDS 2024, a longstanding annual conference by the International AIDS Society (IAS).

This case stands out as the anonymous man and his donor both only have a single copy of the rare CCR5-delta 32 mutation (heterozygous) that prevents HIV from entering cells, which raises the possibility of a more sustainable and less risky cure in the future with an expanded stem cell donor pool.

Stem Cell Transplants in the Future

While each of these cases brings about hope that a cure will be found, providing hope to the estimated 39 million people living with HIV, at this time, a cure is not yet available for most cases.

Currently, stem cell treatments are too risky for those without life-threatening diseases such as cancer. However, with each successful new case, scientists can further investigate and hopefully discover a sustainable cure. The “Next Berlin Patient” study presented by Christian Gaebler of Charité – Universitätsmedizin Berlin, concludes that “effective reservoir reductions, durable HIV remission and potential cure can be achieved with functional viral co-receptors, suggesting that allogeneic immunity fundamentally contributes to HIV eradication.”

HIV Prevention and Vaccines

While research continues to search for a permanent cure that can work across a large variety of HIV cases, there are still effective treatments to help manage the HIV long-term. Antiretroviral therapy (ART) can help keep HIV replication in check indefinitely but does not eradicate the infection from the body. As the virus inserts its genetic blueprint (known as the provirus) into host cells and sets up a latent viral reservoir, it becomes incredibly challenging to eradicate from the host’s body.

Antiretroviral Treatment (ART)

The treatment for HIV is called antiretroviral therapy, or ART for short. ART involves taking a combination of HIV medicines each day, called an HIV treatment regime and is recommended for everyone who has HIV. While ART does not cure the disease, it does allow people with HIV to live longer, healthier lives and also reduces the risk of transmission.

HIV medicines prevent HIV from multiplying or replicating (making copies of itself), reducing the amount of HIV in the body, called the viral load. Less HIV in the body helps the immune system recover and produce more CD4 cells. Though there is some HIV in the body, the immune system is strong enough to fight off infections and certain HIV-related cancers.

Additionally, by reducing the viral load, ART can reduce the chance of transmission. The main goal of HIV treatment is to reduce a person’s viral load to an undetectable level. People with HIV who maintain an undetectable viral load have no risk of transmitting HIV to their HIV-negative partners through sex.

There are many HIV medicines available for treatment regimes, and they are grouped into seven classes according to how they fight HIV. The choice of ART will depend on the individual’s needs, and the person and their healthcare provider work together considering many factors, including possible side effects and potential drug interactions.

The seven groups of HIV medicines are classified as follows:

NNRTIs
NRTIs
PIs
Fusion Inhibitors
CCR5 Antagonists
INSTIs
Post-attachment Inhibitors

Vaccines

While the science community has yet to discover an effective and safe vaccine, work is ongoing to continue the search. Finding a vaccine for HIV is difficult due to the virus’s ever-changing and sneaky nature and ability to disguise itself. Even if antibodies are made, the virus changes to escape them.

Why Are Vaccines So Difficult to Create for HIV?

HIV is a tricky virus and presents various challenges to finding not only a cure but also a vaccine. Some of the challenges scientists face in creating a vaccine are based on the complex nature of HIV itself.

Some of the reasons include:

HIV is not readily recognized on its own by the immune system as dense clumps of sugar molecules hide targets on the virus for neutralizing antibodies
It is genetically varied within and across different populations with different strains and clades of HIV – this is true even with the individual as well as across groups. This makes finding an effective vaccine across multiple types and clades challenging.
HIV inserts its genetic blueprint onto the cells of the immune system, which makes it challenging for a vaccine to target only HIV as it hides itself within the host
No one has ever cleared HIV on its own, making it challenging as there is no natural model of protective immunity on which to base research.

Early vaccines targeted different parts of the virus that induce T cells, which kill the infected cells, but because HIV integrates itself into the host genome, the T cells didn’t recognize the viruses as separate from the host. This ability of the virus hinders the vaccine platforms that can be used, such as live attenuated vaccines. Unlike measles, rubella, and mumps, this type of vaccine cannot be used as the live attenuated virus could integrate into the host cells (DNA) and elicit disease. In addition, as there are different subgroups of HIV, a vaccine that works against one type may not work against another group (or clade) of HIV, yet another challenge.

Over 250 HIV vaccine trials, mostly in the early stages, have assessed whether the vaccine was safe and whether an immune response was shown following vaccination. Very few trials have advanced to the point of assessing efficacy. Of those, there have not been promising results that could see a large-scale vaccine. Two different phase II trials have recently closed early due to disappointing results in 2021 and 2023.

There are ongoing phase I trials, such as with Vir Biotechnology, whose study has dosed the first patient with the new T cell vaccine VIR-1388 to prevent HIV, supported by the Bill and Melinda Gates Foundation. The two-part, placebo-controlled, double-blind, randomized study is being carried out in both US and international sites and has enrolled nearly 95 patients from 18 to 55 years old.

Another trial using mRNA for an HIV vaccine, while ongoing, has run into some struggles due to a skin reaction from participants. However, mRNA vaccines continue to hold promise in research. They work by delivering a piece of genetic material that instructs the body to make a protein fragment of a target pathogen such as HIV, which the immune system recognizes and remembers so it can mount a substantial immune response if later exposed to that pathogen.

Prevention Methods (testing, safe sex, PREP and PEP)

Currently, two preventative medicine regimes help prevent HIV infection from taking hold after exposure.

PrEP or Pre-exposure Prophylaxis: Medicine that is taken daily to prevent getting HIV and reduces the risk of getting HIV from sex by 99% if taken as prescribed. It reduces the risk of getting HIV from injection drugs by at least 74% if taken as prescribed.

PEP or Post-exposure Prophylaxis: Medicine that prevents HIV after possible exposure and is for emergencies only and must be started within 72 hours (3 days) after exposure.

However, researchers continue to look for effective methods to help prevent infection. While PrEP and PEP require taking pills either before (PrEP) or PEP (after), new trials are assessing whether a long-acting shot could help prevent HIV infection transmission. While the traditional methods are highly effective when taken as prescribed, using methods such as Gilead’s Sunlenca could help address stigma and discrimination when storing pills and adherence to PrEP can be a struggle, given its twice-yearly rather than daily schedule.

A trial run by Gilead called Phase III PURPOSE 1 trial of its drug Sunlenca (lenacapavir) prevented 100% of HIV cases in cisgender women. According to Gilead, the long-acting shot was well-tolerated with no significant safety concerns.

Testing

One key pillar to managing any disease is testing. The only way to know one’s status is to test. Ensuring regular testing can help individuals and communities access the treatment needed and help prevent onward infection.

HIV testing is quick and accurate and can detect HIV earlier than past tests, and in the case of INSTI® HIV-1/2 Antibody Test offers results in just one minute! In addition to traditional tests through a lab, rapid tests such as the INSTI® lineup offer options to how and when people can test, offering more flexibility to meet people where they need to be met to ensure that everyone has access to a test to learn their status and make informed health choices that work for themselves and their loved ones.

What’s Next in HIV Cure and Prevention Research

Researchers continue to identify why these seven cases were cured with various stem cell transplants while other attempts have failed, as no single decisive factor is common to all cases.

The current procedure for a transplant is dangerous as the patient’s immune system must be significantly weakened before and after the transplantation. This is an expensive procedure that requires extensive medical care and monitoring, and donors with the double mutation are rare.

The combination of chemotherapy, conditioning regimens, stem cell transplants, immune suppression therapies, and the cancer itself leave patients weakened, often for years afterwards (as it did to the Berlin patient). The London patient was encouraging to researchers as the conditioning regime was considered to be milder, which means that in the future, there is a possibility that more people can access this treatment and may be able to survive and thrive after the combination of the stem cell transplant, the conditioning regime ahead of time, and other immune suppression therapies.

Additionally, researchers have suggested that more targeted and safer therapies may be used instead of the traditional chemotherapy used in conditioning regimes. One concept is the use of highly specialized antibodies developed in a lab and used so far in non-human experiments using mice and monkeys. These antibodies target and disable key cells of the immune system, targeting a protein on the immune system cells called CD117.

Preliminary trials are underway with HIV-negative people with cancer, and in the future, it may be a safe and effective conditional regime for HIV-positive people to receive a stem cell transplant.

As it stands currently, it appears that the CCR5 mutation is a critical aspect of long-term HIV remission and, hopefully, one day, a cure.

There are different approaches to researching a cure for HIV. Some of these will use different methods and approaches, such as gene therapies that make a person’s immune system resistant to most strains of HIV by causing them to stop expressing the CCR5 co-receptor. Another approach is to enhance the immune system’s ability to recognize and kill HIV-infected cells with techniques such as CAR-T cell therapy. Also being researched is a way to help the immune system using highly effective antibodies that target HIV or specific receptors on cells of the immune system, such as alpha4beta7 receptors.

One area of research that shows promise is Monoclonal Antibody Treatment, a passive immunization strategy, which the Vaccine Research Center (VRC) at the National Institute of Health (NIH) is working on. Passive immunity is when a person is given antibodies to a disease rather than producing them through their immune system.

Scientists at VRC found that some people who had been infected with HIV for a long time had highly potent and broadly neutralizing antibodies that recognize many different strains of HIV. Researchers have isolated these antibodies, sequenced them, and produced them synthetically, and in experimental trials, the results have been promising. The issue facing this method is that the monoclonal antibodies are required to be given repeatedly. Currently, researchers are focused on making a vaccine that will induce the body to produce these.

Finally, another approach may be to use germline targeting, which uses a series of primer and booster vaccines to train B cells (the immune system’s antibody factories) to recognize HIV and produce broadly neutralizing antibodies that can deactivate the virus. This focuses on overcoming HIV’s ability to hide by creating immunogens containing viral proteins designed to get a strong immune response. There are a few studies ongoing that use this approach.

In Conclusion

The search for an HIV cure has seen significant progress, with the recent case of the “next Berlin Patient” marking the seventh known instance of someone being cured of HIV following a stem cell transplant. Despite these successes, a universally viable cure remains elusive. HIV presents unique challenges, such as its ability to hide in viral reservoirs and its high mutation rate, making it difficult to eradicate completely.

Research continues to explore various approaches, including gene editing, immune modulation, and stem cell transplants. Stem cell transplants, particularly those involving the CCR5-delta 32 mutation, have shown promise but are currently risky and only used in severe cases. Other experimental methods, like CRISPR gene-editing and monoclonal antibody treatments, are also being tested. Although these advancements offer hope, the search for a safe, widely applicable cure continues, with ongoing efforts to improve HIV prevention and develop an effective vaccine.