The promise and challenge of stem cell transplants in HIV cure

The only confirmed case of HIV cure, and two cases of long-term remission without treatment, are the result of stem cell transplants. In this article, we delve into the world of stem cell transplants and how they are being used in people living with HIV.

To help, we have developed a transplantation glossary to explain many of the common terms:

Transplantation glossary

What is a stem cell?

The bone marrow, found in the centre of the larger bones in the body, is where blood cells develop. The bone marrow is full of stem cells. These cells can develop into many different types of cell, depending on the surrounding environment. Haematopoietic, or blood, stem cells are able to produce all the different cells in the immune system. These include red blood cells, innate immune cells, T cells and antibody-producing B cells.

What is a stem cell transplant?

A transplant involves collecting stem cells from one person (the donor) and transferring them into another person (the recipient). A stem cell transplant replaces a damaged immune system with a new one. It’s a dangerous procedure and a last resort for treating some blood cancers. Donors and recipients must be carefully matched, otherwise the transplant will be rejected.

What does a stem cell transplant involve?

Stem cells are harvested from the donor, usually straight from the blood. This is done after ‘mobilisation’ where the donor is given injections of growth factors. These growth factors stimulate the bone marrow to produce lots of stem cells which leak into the blood. Harvesting the stem cells from the blood is fairly straightforward. Blood is taken out through a tube and passed through a machine that separates out the stem cells. The remaining blood is re-infused into the donor. The stem cells are then ready for transplantation. Stem cells can also be harvested from umbilical cord blood which is a rich source of stem cells.

The recipient is prepared for the transplant through a conditioning process. The conditioning procedure removes the existing stem cells in the bone marrow and gets rid of as much of the cancerous cells as possible. This makes room for the transplanted cells. Various conditioning regimens exist, including chemotherapy, monoclonal antibodies and radiation. Some conditioning regimens are harsher than others.

After conditioning, the stem cells from the donor are infused into the recipient. This process is a bit like a blood donation.

Sometimes, the donor and the recipient are the same person. This type of transplant (autologous) involves harvesting stem cells before a course of immune-damaging treatment is given. The stem cells are then given back after treatment to replenish the immune system.

How is transplant success measured?

The main measure of transplant success is whether the new cells manage to grow and make new blood cells. This process is called engraftment, and takes about 2-6 weeks to fully occur. Engraftment is monitored through regular blood tests. One precise measure of engraftment is to look at chimerism. Chimerism assesses the ratio in the blood of cells from the donor to blood cells from the recipient. Full chimerism is achieved when all of the blood cells come from the donor. Partial or mixed chimerism occurs when some blood cells come from the recipient.

Stem cell transplants in people living with HIV

People living with HIV are at higher risk of developing blood cancers including leukaemias and lymphomas. Some of these people may need a stem cell transplant, but the survival rate is lower than for people without HIV.

Most stem cell transplants for treating people living with HIV are allogeneic, where the donor and the recipient are two separate people. Some gene therapy trials are working on autologous samples, where harvested stem cells are modified then reinfused.

The promise of stem cell transplantation for HIV cure was first highlighted in the case of Timothy Ray Brown, aka the Berlin Patient. In February 2019, Timothy celebrated the 12^th anniversary of his transplant. Since his transplant, he has remained HIV-free and off treatment.

This first instance of HIV cure was momentous. It demonstrated the possibility for someone to become HIV negative after being HIV positive. In the years since Timothy Ray Brown’s cure, there has been an increased focus stem cell transplantation in HIV. International studies are now underway to understand the impact and potential of stem cell transplantation in people living with HIV. This includes the International Collaboration to guide and investigate the potential for HIV cure by Stem Cell Transplantation (IciStem).

Stem cell transplantation is not a procedure that can be extended to the millions of people around the world living with HIV. It can, however, teach us about HIV persistence and the possibilities for HIV cure.

What’s the fuss about CCR5?

HIV uses proteins on its surface to unlock entry into T cells. The primary receptor on T cells is the CD4 molecule. HIV also uses one of two co-receptors – CCR5 and CXCR4. These co-receptors detect chemicals called cytokines that guide cell migration through the body. Most HIV enters CD4 T cells using the CCR5 co-receptor.

There is a naturally occurring variant of CCR5 that is present in a minority of people. The variant is called CCR5Δ32 (pronounced CCR5delta32). This variant has a piece of the gene missing and does not make a functional protein. The CCR5Δ32 variant is found in between 0-16% of the population. It is more common in central and northern Europe and Scandinavia. A few people, like Timothy Ray Brown’s donor, carry two copies of the CCR5Δ32 variant. These people can’t be infected with HIV that needs a CCR5 co-receptor.

The IciStem project screens potential stem cell donors for their CCR5 genotype. They have built a European database of nearly 5 million donors. More than 40,000 of these donors lack functional CCR5 (designated CCR5Δ32/ CCR5Δ32, Δ32/Δ32 or -/-).

A lack of functional CCR5 is an advantage for preventing HIV infection. A recent study in a large population of people of British ancestry, however, suggests that the CCR5 Δ32/Δ32 genotype may also have disadvantages. This large study suggests that people with the CCR5 Δ32/Δ32 genotype have a higher chance of death than those with full CCR5. The exact reasons for this are not yet known but may be due to poor responses to influenza infection.

In the rest of this article, we use -/- to indicate people with two copies of CCR5Δ32; +/- to indicate people with one copy of CCR5Δ32 and +/+ to indicate people with two copies of full CCR5.

What did Timothy Ray Brown teach us?

Timothy received two stem cell transplants to treat both leukaemia and HIV. His transplants came from a -/- donor lacking the CCR5 co-receptor for HIV infection. This clever donor choice meant that Timothy’s new immune cells were effectively resistant to infection with HIV.

This case demonstrated the real risks of transplantation. Timothy’s first transplant was initially successful, but his leukaemia relapsed after about a year. A second transplant was needed. Recovery from the second transplant was rough. Timothy was very unwell. While his HIV did not rebound, he suffered brain and nerve damage.

In the years since the transplant, Timothy has volunteered for multiple studies to find remnants of viable HIV in his body. None have been found. This case demonstrated for the first time that a cure for HIV is possible, though clearly not without risks.

What questions remained?

Timothy Ray Brown’s cure was astonishing but left many questions unanswered. The first was whether his cure would endure. Now twelve years after stopping therapy and after repeated precise and sensitive tests to detect HIV, it is fairly safe to say yes.

Other unanswered questions included:

• What was the role of the conditioning regime in his cure?
• Was his cure achieved because he had two transplants from the same donor?
• Did graft-versus-host disease after the transplant contribute to his cure?
• What was the significance of Timothy’s own CCR5 genotype? (he already had one copy of the CCR5Δ32 gene)
• Would it be possible to do a transplant in people living with HIV without causing terrible illness?
• Could it be repeated?

What have we learnt since?

There are now many documented cases of stem cell transplants in HIV. We have summarise cases where details are available in the figure and table below. Most of these cases are designated by the cities in which the studies took place.

Notable cases of transplantation in people living with HIV

CLICK to enlarge. Cases are grouped by donor type (-/- in red; +/+ in blue and +/- in purple), and by the use of treatment interruption. Periods of treatment interruption are indicated by hashed lines. Cases where the individual is still under follow-up are indicated with an arrow. Blunt-ended lines indicate the person has died.

GvHD = Graft-versus-host disease; TI = treatment interruption; AML = acute myeloid leukaemia; HL = Hodgkin’s lymphoma; NHL = Non-Hodgkin’s lymphoma; ALL = acute lymphoblastic leukaemia; MDS = myelodisplastic syndrome; NK-NHL = NK cell non-Hodgkin’s lymphoma; MA = myeloablative conditioning; RIC = reduced intensity conditioning  

The Boston and Minnesota patients have taught us that transplants from +/+ donors can be infected with HIV. Despite repeated negative tests for HIV, all three showed delayed but vigorous HIV rebound after treatment interruption. This means there was a small but undetectable HIV reservoir in these people after transplant. The reservoir then re-emerged and infected the grafted cells after treatment interruption.

The Münster, Minneapolis, Barcelona, Utrecht and Santiago patients demonstrate the risks of -/- transplants. All of these people died within months of their transplants despite remaining on treatment for HIV.

The IciStem cohort and Australian patients received either +/- or +/+ transplants. These cases have helped demonstrate the reduction of the HIV reservoir after transplantation. Many of these people remain alive and under follow-up.

The Essen patient demonstrated a critical limitation of -/- transplantation. This patient experienced a relapse of lymphoma and stopped therapy. An immediate HIV rebound occurred with a virus using the CXCR4 co-receptor. Clearly, -/- transplantation only protects against HIV using the CCR5 co-receptor. Careful investigation of the type of virus present before transplant is needed.

More recently, the London and Düsseldorf patients show promise in replicating the success of Timothy Ray Brown’s cure. While both of these people continued treatment for the first 1-5 years after transplant, lasting treatment interruption suggests long-term remission. Both of these people had reduced intensity conditioning before their transplant. This suggests that harsh conditioning wasn’t the key to Timothy Ray Brown’s cure. Both of these cases were single transplants, not double like Timothy’s. Neither of these cases experienced severe disease following transplantation, however both had mild graft-versus-host disease. As we follow these cases further, it will become clearer whether they can be considered cured.

Where are we now? What else can we learn about the possibilities for HIV cure?

The tiny number of successful stem cell transplants in people living with HIV tell us a few critical things.

Firstly, it does appear possible, at least in some situations, for someone who has been HIV positive to become HIV negative. This is an important motivation to find out how and why this happens – and extend it to more people!

Secondly, stem cell transplantation can significantly reduce the HIV reservoir. It also reduces HIV-specific immunity. In some cases, seroreversion occurs (where HIV-specific antibodies are no longer detectable). This is important because it may minimise the long-term impact of HIV infection.

It is critical to recognise that stem cell transplantation is risky. All the people living with HIV who have received a stem cell transplant have had an underlying malignancy. Many have not survived long after transplant.

Among the publicised cases of stem cell transplant in people living with HIV, none have been women. Whether additional benefits and risks exist for women we don’t know.

Stem cell transplantation will never be the basis for a widespread HIV cure. However, careful study of people living with HIV who need stem cell transplantation can lead to better understanding of HIV persistence and conditions for elimination. These studies form one piece of the HIV cure puzzle.

ART CCR5 HIV HSCT latency remission research stem cell transplant study T cells treatment interruption viral reservoir