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Different approaches to HIV cure research

When used as directed, modern HIV treatment (antiretroviral therapy, ART) is highly effective at controlling HIV. As ART suppresses HIV, the immune system can mostly repair itself. As a result, researchers project that many ART users will have near-normal life expectancy. What’s more, large well-designed clinical trials have found that people whose HIV is suppressed with ART do not pass on the virus to their sexual partners.

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However, even with ART, HIV can still hide inside cells of the immune system deep within lymph nodes, the spleen, brain and likely other tissues. Scientists refer to the pool of infected cells as the reservoir. Long-term research has found that even in highly adherent people on ART, the reservoir appears to increase in size over a period of decades. In the reservoir, HIV is largely in a quiet or latent state. What’s more, the cells that carry HIV in the reservoir appear to escape notice by the immune system. All of this means that ART helps keep people in overall good health, but the burden of the virus cannot be eradicated by ART alone.

Another concern that scientists have is that even with treated HIV infection there is an excess level of inflammation and activation of the immune system. It is likely that these two factors increase the decline of key organ systems and may make people with HIV more susceptible to developing age-associated conditions at an earlier age.

Ideally, a simple and safe therapy that could cure a person of HIV would be best. However, it is extremely difficult (and dangerous) to cure people with existing technology. Instead, most scientific teams working on HIV cure research are attempting something that is probably more feasible in the medium term. They are developing strategies to help the immune systems of people with HIV better recognize infected cells, destroy them and significantly reduce the size of the viral reservoir. The result of such strategies would hopefully be to allow people periods of time where they would not need to take ART, as their immune systems would keep the virus in check. Some scientists call such a goal a “functional cure,” though perhaps a better description would be to help people achieve virological control of HIV without needing to take ART on a regular basis.

Before delving into different approaches to cure research, here is a bit of background about some of the receptors that HIV uses. Scientists have taken advantage of this knowledge to craft strategies for cure research. 

Know your co-receptors

To infect a cell of the immune system, HIV uses a receptor found on T-cells and other cells of the immune system. The receptor is called CD4. After binding to CD4, HIV needs a co-receptor, either one called CCR5 or CXCR4. Most strains of HIV need the CCR5 co-receptor in order to infect a target cell. Some people have a very rare mutation in their genes, called delta-32, which is found in about 1% of people of northern European ancestry. People with the delta-32 mutation do not have CCR5 on their cells and are largely resistant to HIV infection. Some approaches to HIV cure research try to block or remove the ability of cells of the immune system to make the CCR5 co-receptor.

Now on to different approaches in cure research.

Stem cell transplants

Stem cell transplants are risky. For the purpose of attempting an HIV cure, stem cell transplants are reserved for cases where a person with HIV has a life-threatening cancer for which such a transplant would be helpful (such as leukemia and lymphoma). Doctors who think that the person can survive a stem cell transplant search for a bone marrow donor who has the delta-32 mutation and whose genes are similar to the person with HIV. Making such a match is not easy, so these transplants are uncommon in the field of HIV. What’s more, researchers reserve this intervention for people with a terminal cancer diagnosis because it is dangerous. 

First, the person with HIV has to undergo an intensive course of radiation and/or chemotherapy to destroy their bone marrow (and immune system). This makes them highly susceptible to severe illness from otherwise minor infections. After their bone marrow (and much of their immune system) has been destroyed, the person with HIV can receive a transplant from a suitable donor. If successful, the donated cells can repopulate their bone marrow and create a new immune system that is resistant to HIV because it came from a donor whose immune system did not have CCR5 on their cells.

Even so, sometimes the transplant does not work—transplanted cells can be attacked by surviving residual cells of the old immune system and severe inflammatory reactions can occur that can make the recipient of the transplanted stem cells quite ill.

However, in about a handful of cases, the stem cell transplants from people with the delta-32 mutation have been successful and cures of both HIV and cancer have resulted. 

More recently, doctors have been attempting to cure people with HIV using donors who do not have the delta-32 mutation. 

As explained earlier, stem cell transplants are dangerous and attempted only in certain cases. Because they are so risky, stem cell transplants are not practical for most people with HIV. However, they do help scientists learn more about the immune system and how it can resist HIV. For the foreseeable future, stem cell transplants that attempt to cure HIV will be a research tool.

Inhibitors of checkpoints and other proteins

The immune system has powerful mechanisms to attack infected cells and tumours. Such attacks could easily get out of control and the immune system could inadvertently attack healthy tissue. To reduce the risk of this happening, the immune system has a series of checks and balances that help keep it from getting out of control. One of the ways that excessive activity in the immune system is prevented is with some proteins called checkpoints. Examples of checkpoints are as follows:

  • PD-1 (programmed cell death protein-1)
  • PD-L1 (programmed death-ligand 1)
  • CTLA-4 (cytotoxic T-lymphocyte associated protein 4)
  • TIGIT (T-cell immunoreceptor with Ig and ITIM domains)

Tumours and some chronic viral infections (such as HIV) appear to release chemical signals that cause the immune system to over-express checkpoints. This hinders the immune system’s ability to clear tumours and viruses.

Checkpoint inhibitors have been developed as part of cancer treatment. However, a side effect of checkpoint inhibitor therapy is that it can cause the immune system to attack healthy tissue. 

To minimize this problem, some pharmaceutical companies, such as AbbVie, are testing low doses of checkpoint inhibitors (such as one called budigalimab) that reduce HIV’s ability to weaken the immune system but also minimize attacks on healthy tissue. Budigalimab is an antibody that interferes with the checkpoint called PD-1. 

AbbVie is also testing a therapy that binds to a protein on cells of the immune system. The protein is called alpha4beta7 (a4b7). Lab experiments with cells of the immune system suggest that providing antibodies that can block a4b7 helps protect cells from HIV. By covering this protein with an antibody, HIV cannot sense target cells. Another effect of blocking a4b7 is that cells of the immune system appear to better recognize HIV and therefore can attack it. AbbVie is testing an approach that combines low-dose checkpoint inhibition with antibodies that block a4b7. A preliminary trial of this approach has yielded interesting results—with some people able to remain off ART for more than a year while maintaining virological control of HIV.

Clinical trials of this approach with a large number of people will be needed to find out if it can help the immune system keep HIV under control so that long periods without ART are possible.

Latency reversing agents

As mentioned earlier, although good adherence to ART helps keep HIV suppressed, the virus remains inside a pool of cells it has infected. Inside these cells HIV is in a quiet, or latent, state. It is difficult for the immune system to sense these quietly infected cells. Therefore, some scientists propose a two-step approach to deal with this. First, HIV is brought out of latency with drugs called latency reversing agents. Second, the immune system’s virus-fighting abilities are enhanced with certain treatments or vaccines being developed against HIV. Clinical trials of latency reversing agents are underway.

CAR-T cell therapy

CAR-T cell (chimeric antigen receptor T cell) therapy is based on T-cells that have been genetically engineered in the lab to attack only one target. Initially, CAR-T cell therapy was developed to treat certain forms of cancer. As this has been found to be successful, scientists want to use CAR-T cells on another target: HIV-infected cells.

For CAR-T cell therapy, scientists take a sample of a person’s blood and extract T-cells. They then modify these T-cells and give them the ability to focus on attacking HIV. Furthermore, scientists can make CAR-T cells resistant to HIV infection. The cells are grown and allowed to multiply in the lab, forming billions of cells which can then be infused into a person. 

A barrier that scientists have faced in initial studies of CAR-T cell therapy in HIV is that the modified cells do not persist. However, attempts are underway to address this.

Clinical trials aimed at testing variations of CAR-T cell strategies against HIV are underway.

Super antibodies

Scientists have developed what they call bNAbs (broadly neutralizing antibodies). These antibodies can attack HIV and prevent it from infecting cells. In clinical trials, bNAbs can reduce production of HIV. However, there is the possibility that if bNAbs were used on their own (without anti-HIV drugs) HIV could eventually develop resistance to these antibodies. Clinical trials are underway that combine the use of bNAbs with other therapies or that use several different bNAbs simultaneously. The U.S. National Institutes of Health (NIH) is conducting clinical trials of combinations of bNAbs. It is also facilitating the development of long-acting formulations of these antibodies. 

A potential drawback of bNAbs is that they may not be able to penetrate deep within the brain and lymph nodes where HIV-infected cells can reside. It is possible that studies that combine bNAbs with the drug metformin may be useful (see below).

Metformin

Metformin is a drug that has been used for nearly 60 years to help treat people with diabetes. HIV causes changes to the metabolism of T-cells, so researchers at universities in Montreal were interested in studying metformin’s effect on T-cells in people with HIV. 

Experiments in people with HIV who took metformin and ART found that metformin helped certain T-cells (called CD8+ cells) better recognize HIV-infected cells. Also, lab experiments suggest that metformin could help bNAbs better recognize HIV-infected cells..

The Montreal researchers recommend a randomized, controlled clinical trial of metformin + bNAbs in people with HIV who are using ART.

The purpose of metformin would be to enhance the immune system’s ability to help reduce the reservoir of HIV-infected cells and/or enhance the activity of bNAbs.

Clinical trials are important

The approaches listed above are merely some of the different angles from which scientists are trying to attack HIV so that people with HIV can hopefully have long periods off ART. It is important that people with HIV enroll in clinical trials of cure research to help move the field forward.

A completely different approach to trying to control HIV has recently been published and is detailed in the next article.

—Sean R. Hosein

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