New case of HIV cure: combined forces of haploidentical stem cells and HLA incompatible cord blood

Recently, Hsu et al. reported remission and possible cure of HIV-1 infection in the setting of allogeneic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia (AML).¹ This is the fourth case of a potential cure for HIV infection, the first in a woman, the first in a person of mixed race and the first in which a CCR5Δ32/Δ32 haplo-cord transplant was used. .

According to UNAIDS epidemiological estimates for 2022, 38.4 million people are currently living with HIV. After infection, the virus persists in latent pools of resting CD4⁺ Memory T cells for a lifetime. With antiretroviral therapy (ART), the viral load can be reduced below the detection limit, allowing people living with HIV (PLHIV) to lead lives largely free of disease.

To date, three cases of HIV cure have been described (Fig. 1). In all cases, acute myeloid leukemia (AML) was treated using an unrelated homozygous CCR5Δ32/Δ32 allograft. Homozygous carriers of the Δ32 deletion in the CCR5 co-receptor of HIV (0.8 to 1% of individuals of northern European origin) are resistant to CCR5 mainly transmitted using (“R5-tropic”) strains. Thus, no rebound of infection from the remaining reservoirs was detectable even when ART was discontinued due to newly established resistance.

Individual curative trials of HIV-1. In all cases listed, with the exception of the two “patients from Boston” and the “patient from Essen”, a cure of the HIV-1 infection can be assumed so far. The “Berlin patient” succumbed to a relapse of his AML 12 years after his treatment. In general, the effectiveness of curing HIV-1 by stem cell transplantation is difficult to assess because, on the one hand, patients often succumb to complications related to GCS (and consequently the cure of the infection cannot be demonstrated) and, on the other hand, it is possible that some unsuccessful attempts have not been published. The probability of finding an HLA-compatible unrelated adult donor is given regardless of the CCR5 genotype. Wild-type WT, Δ32 CCR5 frameshift mutation, UCT umbilical cord blood transplant

The number of potential adult donors for hematopoietic cell transplantation is relatively small because a very close human leukocyte antigen (HLA) match is required for 8 out of 8 or 7 out of 8 alleles. umbilical cord (UCT) does not require such a strict HLA match between donor and recipient.² In addition, it causes little graft versus host disease (GvHD) and less disease recurrence. However, a limited number of progenitor cells in umbilical cord blood can lead to delayed and unpredictable recovery. Additionally, transfer of adoptive donor T cells for the treatment of viral infections or relapses after transplantation is not available.

Hsu et al. now used an improved variant of the CPU, where in parallel CD34⁺ cells from a haploidentical donor were transplanted.¹ Supportive co-transplantation of CD34 purified peripheral blood⁺ (CD34 is a marker for hematopoietic stem cells) from an HLA-haploidentical donor leads to early recovery of neutrophils and thus bridges the gap between pre-transplant conditioning (eradication of residual leukemia cells and suppression of the immunity of the host to avoid rejection) and transplantation of UCT cells which reduces the risk of infectious complications caused by prolonged neutropenia.

To test the potential of haplo-cord stem cell transplantation for the cure of HIV, the present observational study recruited HIV-1 infected individuals who required allogeneic stem cell transplantation due to a disease underlying malignancy. Two middle-aged HIV-1 positive patients were treated: a man who developed Hodgkin’s lymphoma and a woman who developed AML. Both patients underwent haplo-cord transplantation with CCR5Δ32/Δ32 cord blood units. The man lost the CCR5Δ32/Δ32 graft and died of recurrent Hodgkin’s lymphoma within a year. In the case of the woman, the transplant process was not complicated. Initially, two weeks after treatment, 82% of her lymph lines and 98% of her myeloid lines were from the haploidentical donor, while after 14 weeks, 100% engraftment with the umbilical cord cell line was reported. Of note, comparable to the “Berlin patient”, the patient in this case received whole body irradiation in addition to chemotherapy for conditioning, which was not used in the “London” and ” Düsseldorf” to accommodate the increased risk of rejection. due to HLA mismatch.³ After a 3-year period with undetectable HIV RNA levels, the patient decided to stop ART. HIV-1 RNA levels remained undetectable following treatment, indicating HIV-1 remission and possible cure.

The authors draw particular attention to the implications of their study for racial equity in health, as the likelihood of finding an HLA-matched donor is lower among people of diverse ancestry. Less stringent matching requirements in UCT widen the circle of possible recipients of CCR5Δ32/Δ32 stem cell therapy in PLHIV. The authors further emphasize that their patient never developed GvHD. GvHD was considered critical for the cure of HIV-1 in the Berlin patient due to the underlying graft-vs. HIV”). In the present case, however, GvHD was not a prerequisite for potential cure, and thus the optimized UCT method appears particularly safe, without the adverse sequelae of GvHD. This is consistent with the results of a phase II trial combining haploidentical peripheral stem cells and an HLA-mismatched UCT showing a low relapse rate despite the absence of clinical symptoms of graft versus host disease in a significant proportion of patients.⁴

In the case of the “patient from Essen”, recovery from HIV-1 infection failed, because a rebound of the previously undetected CXCR4-tropic virus occurred after transplantation with adult stem cells CCR5Δ32/ Δ32. In the present case, the autologous virus was exclusively CCR5-tropic and therefore could not infect the grafted CCR5Δ32/Δ32 cells. Unexpectedly, the cells were also not susceptible to a CXCR4-tropic laboratory strain in vitro. This has not been observed in CCR5Δ32/Δ32 adult stem cell transplantation and is another advantage of UCT that could be beneficial in cases like the “Essen patient”. For the present case, it is to be hoped that X4-tropic viruses do not rebound from reservoirs not cleared over an extended period of observation.

So far so good, but it seems this case is just another case of blessing in disguise. So what are the current prospects for curative therapy against HIV? It is likely that modern immunotherapy approaches represent a less risky route to HIV cure for PHAs, but without serious secondary illnesses.⁵ Therapeutic concepts based on adoptive cell transfer (ACT) include the application of chimeric antigen-receiving T cells capable of recognizing and eliminating HIV-infected cells. However, such therapies likely require the use of latency reversal agents, which may have toxic side effects. ACT also opens up the possibility of direct manipulation of isolated T cells using genome editing (e.g. via CRISPR-Cas9), either to directly target the integrated provirus or to generate resistant cells (e.g. example, by introducing the CCR5Δ32 deletion), but are difficult due to the risk of off-target effects. Thus, despite encouraging progress with new curative strategies, questions of safety and efficacy remain challenging.

In summary, with their UCT-based therapy, Hsu et al. successfully demonstrated the feasibility of an alternative strategy for the cure of HIV-1, facilitating the inclusion of mixed-race patients, informing future developments in the field of gene and cell therapy, and raising hopes for greater number of cases of remission and long-term cure .