Cord Blood as a Cure for HIV

Contrary to the impression that may be given by numerous recent headlines on this topic, cord blood is not likely to become a routine therapy for Human Immunodeficiency Virus (HIV), the infection that leads to Acquired Immunodeficiency Syndrome (AIDS).

On 15 Feb. 2022, a team of doctors announced that a woman who received a cord blood transplant in August 2017, at Weill Cornell Medical Center in New York City,  is now cured of HIV^1-4. This “New York patient” is the 4^th person that has been cured of HIV after a stem cell transplant, and the first time that cord blood was used as the stem cell source. It is hoped that this approach will save more lives, but only a tiny fraction of HIV patients will be eligible for this new therapy.

Studies have shown that the standard procedure for giving a stem cell transplant fails to cure HIV^5,6. The premise of all transplants with blood-forming hematopoietic stem cells (HSCT) is to replace the patient’s faulty immune system with a new one. Transplants are very successful when the patient’s immune system is faulty because of a condition like leukemia⁷. The cancerous blood cells that generate leukemia reside in the bone marrow, and a transplant introduces healthy stem cells which migrate to the bone marrow and replace them. It is not as simple to eradicate HIV, because the virus hides in dormant reservoirs in the body and comes back after transplant^1,5,6. The tactic used to cure HIV via transplant is to give stem cells which carry a genetic mutation that will render the new immune system resistant to HIV. That way, if the HIV becomes active again in the patient’s body, the patient’s immune system will have a natural ability to fight it.

Even with the help of a genetic mutation to fight HIV, there is still the problem that stem cell transplants are risky. As doctors say, they carry significant morbidity and mortality, or in plain language about 20% of leukemia patients die of transplant-related causes, regardless of whether their graft source was bone marrow or cord blood⁷. It is safer to treat the majority of HIV patients with Anti-Retroviral Therapy (ART). The only HIV patients that are considered candidates for stem cell transplants are those that become sick with a blood cancer, like leukemia or lymphoma, in addition to HIV.

Moreover, the genetic mutation called CCR5-Δ32 (also known as CCR5 delta 32) that confers natural resistance to HIV is rare⁸. The receptor CCR5 enables the most common strains of HIV to bind to cells. A deletion of 32 nucleotides in the CCR5 gene, denoted CCR5-Δ32, results in a truncated protein that is not expressed on the cell surface. When an individual has two genes that both have the CCR5-Δ32 mutation (the mutation is called homozygous when it appears in both genes), that person is resistant to most HIV infections. However, less than 1% of the world’s population has this double mutation. This mutation must have developed recently in human history, because it is not smoothly distributed across the human race. It is present at frequencies of 12–15% in populations of northern European origin, at frequencies of 2–5% in the Near East and India, and is absent elsewhere apart from isolated occurrences that are probably the result of recent European gene flow⁸. This certainly poses problems when trying to cure HIV patients from non-Caucasian backgrounds.

The “Berlin patient” Timothy Ray Brown became the first person cured of HIV after he received a bone marrow transplant carrying the CCR5-Δ32 mutation in 2007 because he had AML leukemia^9,10. His case was published in 2009, but it was a decade until two more HIV cures were published in 2019. One was the “London patient” Adam Castillejo, who had a bone marrow transplant in May 2016 with the CCR5-Δ32 mutation to treat Hodgkin’s lymphoma^11,12.  The other was an anonymous man in Düsseldorf Germany, who had AML, and was cured of HIV after a bone marrow transplant in 2013 with the CCR5-Δ32 mutation¹³.

The New York patient cured of HIV after a cord blood transplant in 2017 is a significant medical advance for several reasons. The most obvious is that the patient is an African-American woman, so that finding a matching bone marrow donor that carried the CCR5-Δ32 mutation which occurs in northern Europeans was not possible. Instead, she was enrolled in clinical trial NCT02140944, and a cord blood unit was found that was a close enough match for a transplant and that also had the CCR5-Δ32 mutation.

The ability to find a cord blood unit carrying the CCR5-Δ32 mutation was not a coincidence, but was the culmination of a long research project by a consortium of public cord blood banks¹⁴. When the HIV cure of the Berlin patient was first announced, it spurred a group of leaders in cord blood transplantation to launch a project in which tiny blood samples from cord blood banks around the world were sent to a single laboratory for genetic testing. In 2012 they reported that they had tested 18,000 cord blood units, primarily from Caucasian donors, and found 134 that were homozygous for the CCR5-Δ32 mutation¹⁴. They predicted that testing an additional 25,000 units from Caucasians should increase the special inventory to 300 units.

Even with a special cord blood unit that is homozygous for the CCR5-Δ32 mutation, the New York patient needed an extra boost to help her survive the transplant. It is well known that cord blood takes longer than bone marrow to engraft, leaving the transplant patient vulnerable to opportunistic infections¹⁵. To prevent that complication, this patient received bone marrow from a half-matched (haploidentical) adult donor in addition to the cord blood^1,4. This is called a haplo-cord transplant. At first the adult stem cells are dominant and quickly build up the patient’s immune system, but as the cord blood engrafts it takes over and becomes the permanent immune system.  

Another remarkable aspect of the New York patient’s case is that she recovered very quickly and was discharged from the hospital a mere 17 days after the transplant, and did not experience any graft versus host disease (GvHD)⁴.  By comparison, the previous three men cured of HIV after bone marrow transplants all suffered from GvHD^9-13.

The New York patient was first published without fanfare as a conference poster in November 2018, where she was reported to be in “remission” from HIV⁴.  On 15 February 2022, after 4.5 years without detectable HIV, the case was announced as a “cure” at the annual Conference on Retroviruses and Opportunistic Infections¹.

AIDS-related illnesses have killed more than 32 million people since 1981. There are over 37.9 million people living with HIV worldwide, including 1.2 million in the United States^16-18. Within the United States, only 28% of HIV patients are Caucasian¹⁷. The use of cord blood as the graft source for stem cell transplants with the CCR5-Δ32 mutation will expand transplant access to more HIV patients from a wider range of racial backgrounds.

Despite the excitement about cord blood as a therapy for HIV, it must be emphasized that only HIV patients that also have blood cancers are eligible for stem cell transplants. The medical team responsible for the cure of the New York patient has said that this treatment protocol will only be applicable to a few dozen people per year¹. It also must be cautioned that stem cell transplants for HIV are an area of ongoing research, where the complex interactions of many factors are still being sorted. Some of these factors are how to maintain anti-viral therapy during chemotherapy, how to pick the optimal stem cell donor, whether or not GvHD is beneficial, and how to measure whether the HIV has truly been sterilized or is simply in functional remission¹⁸.  Researchers also ask whether future therapies will gene edit the transplant graft, to save the effort of finding donors that have the homozygous CCR5-Δ32 mutation¹⁸? For now, doctors hope that the use of haplo-cord transplants will save the lives of more HIV patients that have blood cancers.

References:

1. Ryan B. Scientists have possibly cured HIV in a woman for the first time. NBC News. Published 2022-02-15
2. Reuters Woman cured of HIV after novel stem cell transplant. YouTube. Published 2022-02-16
3. Philipose R. Explained: How umbilical cord blood was used to cure an HIV patient. IndianEXPRESS Published 2022-02-24
4. Hsu J, Glesby M, Shore TB, Small C, Gergis U, Mayer SA, Phillips AA, Petz LD, Browning R, Warshaw M, Persaud D, Bryson Y, Van Besien K. CCR5 delta32 Cord & Haploidentical Grafts: Allogeneic Stem Cell Transplant for HIV+ /AML Patient: A Case Report from the Impaact P1107 Observational Study. Blood 2018; 132(S1):2184
5. Hütter G. Transplantation of CCR5-A32/A32 Stem Cells May Cure HIV Infection. Stem Cells and Cancer Stem Cells 2015; 13:35-41.
6. Eberhard JM et al. Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1. Science Translational Medicine 2020; 12(542):eaay9355
7. Eapen M, Rubinstein P, Zhang M-J, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 2007; 369(9577):1947-1954.
8. Martinson JJ, Hong L Karanicolas R, Moore JP, Kostrikis LG. Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype. AIDS 2000; 14(5):483-489.
9. Hütter G. et al. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. NEJM 2009; 360:692-698.
10. McCormack K. Remembering a stem cell pioneer in the fight against HIV/AIDS. The Stem Cellar CIRM blog. Published 2020-10-02
11. Gupta RK et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 2019; 568:244–248.
12. Mandavilli A. The ‘London Patient,’ Cured of H.I.V., Reveals His Identity. NYTimes Published 2020-11-09
13. Jensen B. et al. Analytic treatment interruption after allogeneic CCR5-D32 HSCT for AML in 2013. Proceedings of the Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, WA 2019.
14. Petz LD, Redei I, Bryson Y,  ... Chow R. Hematopoietic Cell Transplantation with Cord Blood for Cure of HIV Infections. Biol. Blood Marrow Transp. 2013; 19(3):393-397.
15. Verter F. Omidubicel from Gamida Cell leads the way to Cord Blood Transplant version 2.0. Parent's Guide to Cord Blood Foundation Newsletter Published 2020-06
16. Centers for Disease Control. About HIV. Last updated 2021-06-01
17. Kaiser Family Foundation. The HIV/AIDS Epidemic in the United States: The Basics. KFF website Published 2021-06-07
18. Kalidasan V, Das KT. Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure? Frontiers in Microbiology 2020; 11:46.