Reacción a "A stem cell transplant with only one protective mutation achieves remission of HIV in a cancer patient"

The article by Gaebler et al., published in Nature, describes a new case of HIV remission in a patient treated with an allogeneic hematopoietic stem cell transplant (allo-HSCT) for acute myeloid leukemia.

This is the seventh described case of potential HIV eradication and is called “Berlin 2,” as it was treated in that city and in remembrance of the “Berlin patient,” Timothy Brown, the first patient in whom HIV eradication was reported after a hematopoietic stem cell transplant.

As with any exceptional case in which large quantities of biological material are available, a series of studies can be conducted to explore the potential mechanisms involved in the cure. Furthermore, since these are clinical cases, each patient has particular characteristics that make them different from the others.

The authors highlight that the Berlin 2 patient received a transplant from a donor who was not homozygous for the delta 32 mutation in CCR5, unlike previously reported cases of possible cure. CCR5 is the HIV receptor, and a percentage of the population (0.4–1% homozygous in Caucasians) has a genetic defect that prevents the expression of this receptor. These individuals are practically resistant to HIV infection, since the variants that use the other receptor—CXCR4—are rare and have limited capacity for acute infection.

For this reason, it has been suggested that, in the context of allo-HSCT, having a donor homozygous for this gene is an important, if not definitive, factor. Other factors postulated for achieving a cure include aggressive pre-transplant conditioning therapy, the development of potent graft-versus-host disease (GVHD) that could lead to the destruction of residual infected cells, or post-transplant immunosuppressive therapy to control GVHD.

A homozygous donor could not be found for this patient, but a heterozygous donor—possessing one normal and one mutant gene—was available, which reduces the virus's infectivity, as discussed later. Given this option, it was decided to perform the transplant with this donor. The positive outcome leads the authors to propose that homozygosity for the CCR5 deletion should not be an essential requirement for donor selection and that heterozygosity should be considered as an option. However, there is already at least one case in which the transplant was not performed with a donor without mutations in the CCR5 gene, the so-called "Geneva patient" (Saez Cirion A et al. Nat Med 2024). Although the follow-up period was 32 months, a complete remission was observed, which diminishes the originality of this newly described case.

Regarding the receptor, it has several particularities. The reported case is characterized by its original genetic makeup, which was heterozygous for the CCR5 receptor. This does not make it resistant to infection, but it has been described that in these individuals the infection is less aggressive, since the number of "entry points" in the cell is reduced. This is consistent with the evolution of HIV infection in this subject, who was untreated for five years and maintained spontaneous HIV replication at a low level (2,000-20,000 viral RNA copies/ml) and a CD4 count greater than 500 cells/µL. The patient acted as a viremic controller of HIV, without an aggressive progression of the infection.

The post-transplant study describes a progressive decline in the HIV reservoir until only trace amounts were found (levels of 0.07 copies per million CD4 cells) and the inability to isolate a replicating virus in a mass of 130 million CD4 cells. Furthermore, the presence of sequences of the viral variant that uses the other receptor (CXCR4) was also very low. These data strongly suggest that the allogeneic transplant has eradicated HIV from the body, although longer-term follow-up will be necessary to confirm this.

Could other mechanisms have contributed to the control of the virus? The pre-transplant conditioning was intense but not extreme, and graft-versus-host disease was mild and treated with Cyclosporine A, so these factors likely played a less significant role. The immune response against HIV gradually disappeared post-transplant, which is expected when the virus is eliminated. The authors highlight the existence of a subpopulation of cells called natural killer cells (ADCC) with high antiviral activity, which was detected in post-transplant samples. They suggest that these cells may have contributed to the destruction of the minority of infected cells that survived the transplant, although this remains highly hypothetical.

In summary, this is yet another case, with interesting characteristics but one that doesn't contribute significantly to the field. As mentioned, the heterozygosity (or non-homozygosity) of the donor cells is not a novel finding, as there is a known case in remission that was transplanted with cells without any mutation in the CCR5 gene.

These cases, due to their exceptional nature, are studied and contribute to our knowledge, but they sometimes raise false expectations in people with HIV.

It is important to reiterate that this treatment cannot be extrapolated to people with HIV who do not require a transplant for other reasons. HIV infection is perfectly controlled with drug treatment, and transplantation is not an option, given its high mortality rate, unless the patient has a malignant hematological disease that necessitates it.