A New Case for HIV Cure: Linkage of Haploidentical Stem Cells and HLA-mismatched Cord Blood

Recently, Hsu et al.. reported the potential for remission and cure of HIV-1 infection in the context of allogeneic hematopoietic stem cell transplantation for the treatment of acute myeloid leukemia (AML).¹ This is the fourth historical case of a confirmed potential cure for HIV infection, the first in a woman, the first in a mixed race, and the first time a CCR5Δ32/Δ32 haplocode transplant has been used.

According to UNAIDS 2022 epidemiological estimates, 38.4 million people are currently living with HIV. After infection, the virus remains in her dormant CD4 potential reservoir.⁺ T memory cells are used for lifetime. Antiretroviral therapy (ART) can reduce the viral load to undetectable levels, allowing people living with HIV (PLWH) to live largely free from the effects of the disease.

To date, 3 cured cases of HIV have been reported (Fig. 1). 1). In all cases, acute myeloid leukemia (AML) was treated using unrelated homozygous CCR5Δ32/Δ32 allografts. Homozygous carriers of the Δ32 deletion of the co-receptor CCR5 of HIV (0.8–1% of individuals of Nordic descent) are resistant to her CCR5-using (“R5-tropic”) strains that are predominantly transmitted there is. Thus, even when ART was discontinued due to newly established resistance, we could not detect a rebound of infection from remaining carriers.

An individualized treatment trial for HIV-1. In all of the cases listed, except for her two, the “Boston patient” and the “Essen patient,” cures of her HIV-1 infection have thus far been assumed. The ‘Berlin patient’ died of recurrence of AML 12 years after treatment. In general, it is difficult to assess the efficacy of stem cell transplantation for curing HIV-1. The reason is that, on the one hand, patients often die from complications associated with her SCT (thus not demonstrating cure of the infection), and on the other hand. However, some of the failed attempts may not have been published. The chance of finding an HLA-matched unrelated adult donor is given regardless of CCR5 genotype. WT wild-type, Δ32 CCR5 frameshift mutation, UCT cord blood transplant

The number of potential adult donors for hematopoietic cell transplantation is relatively small. This is because 8 out of 8 alleles or 7 out of 8 alleles must have very good human leukocyte antigen (HLA) matches. In contrast, transplantation of stem cells from the umbilical cord (UCT) does not require strict HLA matching between donor and recipient.² In addition, it causes less graft-versus-host disease (GvHD) and less disease recurrence. However, the limited number of progenitor cells in cord blood can make recovery slow and unpredictable. Additionally, adoptive donor T-cell transplantation to treat viral infections or post-transplant relapses is not available.

Sue et al. Now he uses an improved version of UCT, and in parallel he uses CD34⁺ Cells from haploidentical donors were transplanted.¹ Adjuvant co-transplantation of purified peripheral blood CD34⁺ Cells from HLA haploidentical donors (CD34 is a marker for hematopoietic stem cells) lead to early recovery of neutrophils, pre-transplant conditioning (eradication of residual leukemia cells and suppression of host immunity to prevent rejection) and UCT. fill the gap between engraftment. Cells that reduce the risk of infectious complications caused by long-term neutropenia.

To test the potential of haplocode stem cell transplantation for curing HIV, this observational study enrolled HIV-1-infected individuals who required allogeneic stem cell transplantation for underlying malignancies. Two HIV-1-positive middle-aged patients were treated: a man with Hodgkin’s lymphoma and a woman with AML. Both patients underwent haplo-umbilical cord transplantation using the CCR5Δ32/Δ32 cord blood unit. The man lost his CCR5Δ32/Δ32 graft and died within a year of recurrent Hodgkin’s lymphoma. For women, the transplant process was uncomplicated. Initially, after 2 weeks of treatment, 82% of her lymphoid lineage and 98% of myeloid lineage were derived from haploidentical donors, and after 14 weeks, 100% engraftment of her umbilical cord cell lineage was reported. Of note, like the ‘Berlin patient’, the patient in this case received total-body irradiation in addition to conditioning chemotherapy, whereas the ‘London’ and ‘Düsseldorf’ patients It has not been done to adjust for increased risk of rejection. Due to HLA mismatch.³ After three years of undetectable HIV RNA levels, the patient decided to discontinue ART. HIV-1 RNA levels remained undetectable over time, indicating that HIV-1 may be in remission and may be cured.

The authors pay particular attention to the study’s implications for racial health equity, as individuals of diverse ancestry are less likely to find HLA-matched donors. Less stringent match requirements in UCT broaden the pool of potential candidates for CCR5Δ32/Δ32 stem cell therapy in PLWH. The authors further emphasize that the patient never developed GvHD. GvHD is important for HIV-1 cure in Berlin patients because the underlying graft-versus-leukemia response also eradicates residual host T cells that may have been infected with HIV (the ‘graft-versus-HIV effect’). It was thought that there was. However, since GvHD was not a prerequisite for possible cure in this case, his optimized UCT method appears to be particularly safe without the unwanted sequelae of her GvHD. This is consistent with the results of a phase II trial combining haploidentical peripheral stem cells and HLA-mismatched UCT, which showed a low recurrence rate despite the lack of clinical manifestations of graft-versus-host disease in a significant proportion of patients. I am doing it.^Four

In the ‘Essen patient’, cure of HIV-1 infection failed because a previously undetected rebound of CXCR4-tropic virus occurred after transplantation of adult CCR5Δ32/Δ32 stem cells. In this case, the autologous virus was exclusively CCR5-tropic and thus failed to infect her transplanted CCR5Δ32/Δ32 cells. Unexpectedly, cells were also insensitive to CXCR4-directed laboratory strains in vitro. This has not been observed in adult CCR5Δ32/Δ32 stem cell transplantation and constitutes another advantage of UCT that may be advantageous in such cases as the ‘Essen patient’. In the present case, it is hoped that the X4-tropic virus does not rebound from an uncleared source during the long-term observation period.

So far so good, but it looks like this case is just another blessing in disguise. So what are the prospects for HIV curative therapy at this point?Perhaps modern immunotherapeutic approaches are less risky to cure PLWH of her HIV, without severe secondary disease? showing you how.^Five A therapeutic concept based on adoptive cell transfer (ACT) involves the application of chimeric antigen receptor T cells that can recognize and eliminate HIV-infected cells. However, such treatments may require the use of potency-reversing drugs and 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) to directly target integrated proviruses or generate resistant cells ( e.g. by introducing a CCR5Δ32 deletion) is difficult due to the risk of off-target effects. Therefore, despite the accelerated progress of newer therapeutic strategies, safety and efficacy issues remain a challenge.

In summary, using UCT-based therapies, Hsu et al. demonstrated the feasibility of alternative strategies for HIV-1 treatment, facilitated the acceptance of mixed-race patients, and contributed to the further development of the field of gene and cell therapy. and raised hopes for more long-term remissions and cures. .