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A second person in Berlin is cured

In June 2009, doctors published details on the first patient that would later become cured of HIV. His cure was effected through a stem cell transplant with a rare mutation, as well as a complex and at times toxic mix of chemotherapy, radiation and other interventions. The reason this patient was cured was likely because he received a stem cell transplant from a donor who lacked a co-receptor that is used by most strains of HIV to infect cells. This co-receptor is called CCR5. Such donors have a very rare mutation that allows them to live without having cells with this co-receptor. Scientists call this rare mutation delta-32. People with both copies of a gene with the delta-32 mutation are rare; it is found in about 1% of people of northern European descent. People with only one copy of a gene with the delta-32 mutation are a bit more common—about 10% of European populations have this. Some parts of the world, such as South Africa and Chile, have small populations with this gene because of migration. (For more about HIV co-receptors, see the earlier article “Different approaches to HIV cure research.”)

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Subsequently, five out of seven people who have received a stem cell transplant from a donor with genes that have both copies of the delta-32 mutation (along with an intensive course of radiation and chemotherapy) have also been cured of HIV. In the long history of attempts at curing HIV, giving a person a stem cell transplant without both copies of the delta-32 mutation has not worked.

Note that attempts at cure are difficult and dangerous, as they involve destroying a person’s bone marrow (the source of the cells that ultimately form one’s immune system). Not only that, but the donor of the stem cells must be genetically similar to the recipient. This genetic relatedness is necessary to reduce the risk of the recipient’s immune system destroying the transplanted cells. Doctors usually only attempt stem cell transplants to try to cure HIV in people who have a life-threatening cancer (whereby the cancer can also be cured with a stem cell transplant, such as cases of leukemia and lymphoma).

Prospective recipients of a stem cell transplant must first undergo the destruction of their bone marrow (with radiation and/or chemotherapy). The loss of their immune system places them at risk for serious infections. They can then be given the stem cell transplant. But it takes time to recreate their new immune system. To prevent the residue of their old immune system from attacking the donated stem cells, their immune systems are temporarily suppressed. HIV treatment (antiretroviral therapy, ART) is taken during these procedures to minimize the risk of the virus infecting their new immune system. Several years after the transplant, when doctors can no longer detect HIV in the blood and from biopsy samples, ART is withheld to see if any HIV becomes detectable. 

As mentioned earlier, a handful of people have been cured with stem cell transplants from donors with genes that have both copies of the delta-32 mutation. 

Last year there was a report of a patient in Geneva being in what scientists call “remission” from HIV. After the stem cell transplant and associated procedures, doctors were unable to find HIV after they withheld ART. What makes the Geneva patient interesting is that he received a stem cell transplant from a donor who did not have the delta-32 mutation. This mutation largely renders a person’s immune system resistant to HIV infection. The new immune system of the Geneva patient does not have the delta-32 mutation; therefore, it is still susceptible to HIV, but researchers are unable to find any virus in his blood and tissue samples.

The researchers theorize that the reaction between the remnants of his old immune system and the donated stem cells—a reaction called graft vs. host disease—probably helped to kill HIV-infected cells.

In Berlin

Doctors in Berlin recently reported details on a patient who was diagnosed with HIV in 2009. He began ART in 2015 with a combination of raltegravir, abacavir and 3TC, and his viral load was subsequently less than 50 copies/mL. In April of that year he was diagnosed with a form of leukemia that would prove lethal if left untreated. Analysis of the HIV in his blood samples revealed that 99.7% of viruses used CCR5. This suggested to the doctors that he would benefit from a stem cell transplant from a donor whose cells lacked CCR5 (that is, someone with the delta-32 mutation).

Doctors sought a donor who was genetically similar to the patient and whose cells had both genes with the delta-32 mutation. They were unable to find such a donor. However, they did find someone whose genes had one copy of the delta-32 mutation (the previous successful stem cell transplants that led to HIV cures were with donated stem cells that had two copies of the mutated gene).

The patient developed what doctors described as mild complications from the transplant.  Within 28 days, the transplanted stem cells began to repopulate his immune system. His leukemia was cured, as usually happens with a stem cell transplant.

Over time, doctors could not find HIV in his blood after the transplant, so in September 2018 he stopped taking ART. Subsequently, doctors were not able to find HIV in his blood samples and biopsies of lymph nodes. What’s more, the patient’s T-cells did not recognize HIV when exposed to the virus in lab experiments. This suggests that his T-cells did not encounter the virus since the stem cell transplant.

It has been six years since the patient stopped taking ART, and researchers have not been able to find HIV in his body. They think that he is potentially cured of HIV.

Bear in mind

Researchers are not certain why the patient was cured, as the stem cell transplant lacked cells with both copies of the delta-32 mutation in their genes. However, research on this patient and his blood samples is promising and may yield clues for new therapies and interventions that are simpler and safer for curing HIV.

—Sean R. Hosein

REFERENCES:

  1. Gaebler C, Kor S, Allers K, et al. The next Berlin patient: sustained HIV remission surpassing five years without antiretroviral therapy after heterozygous CCR5 WT/Δ32 allogeneic hematopoietic stem cell transplantation. 25th International Conference on AIDS, Munich, Germany, 22-26 July 2024. Abstract SSO4O2LB.
  2. Jasinska AJ, Pandrea I, Apetrei C. CCR5 as a coreceptor for human immunodeficiency virus and simian immunodeficiency viruses: A prototypic love-hate affair. Frontiers in Immunology. 2022 Jan 27; 13:835994. 
  3. Hütter G, Bodor J, Ledger S, et al. CCR5 targeted cell therapy for HIV and prevention of viral escape. Viruses. 2015 Jul 27;7(8):4186-203. 
  4. Huyveneers LEP, Bruns A, Stam A. Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1. Science Translational Medicine. 2020 May 6;12(542):eaay9355. 
  5. Claireaux M, Robinot R, Kervevan J, et al. Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry. Nature Communications. 2022 Jan 26;13(1):521.