Curating evidence for a cure of HIV-1 infection by hematopoietic stem cell transplantation

Abstract

A cure of HIV-1 infection has previously been described in two individuals undergoing allogeneic hematopoietic stem cell transplants from homozygous carriers of the CCR5D32 gene variant, which confers HIV-1 resistance. Two recent reports corroborate these earlier studies, underscoring that in HIV-1-infected persons with hematologic malignancies, these procedures may provide a realistic perspective for a cure of HIV-1 infection.

Development of a cure for HIV-1 infection has been hindered for decades because of the virus’s ability to establish a reservoir of latently infected cells, which is extremely difficult to target therapeutically. HIV-1 integrates into the chromosomal DNA of infected memory CD4 T cells, where it can persist indefinitely as a transcriptionally silent provirus. In this latent form, HIV-1 remains poorly visible to host immune cells and is unaffected by currently available antiretroviral drugs. However, interruption or termination of ART almost always leads to a rebound of viremia and re-establishment of infection because of the persistence of these latently infected HIV-1 cells; therefore, effective therapy for HIV-1 infection requires life-long treatment with antiretroviral suppression therapy. Targeting and clearing this HIV-1 reservoir is a significant focus for the scientific community.

In the past, two individuals had been designated as cured of HIV-1 infection; they were observed to have no detectable HIV-1 reservoir cells and no viral rebound following ART interruption.^1,2 These two individuals (colloquially referred to as ‘‘the Berlin patient’’ and ‘‘the London patient’’) both suffered from hematologic malignancies and received hematopoietic allogeneic stem cell transplants (HSCTs) from donors homozygous for the CCR5∆32 mutation. Homozygous carriers of this genetic variant represent approximately 1% of all European Caucasians; the deletion is not associated with any known disease but deleteriously truncates the CCR5 co-receptor,^3,4 resulting in resistance to infection with CCR5-tropic HIV-1 strains (Figure 1A). In the Berlin patient, such a procedure resulted in a sustained, drug-free remission of HIV-1 for 13 years; in the London patient, continuous, drug-free control of HIV-1 replication has now been documented for 5.5 years.

Figure 1. Hematopoietic stem cell transplant from CCR5∆32 homozygous donors can be used to cure HIV-1.

(A) CCR5 is a co-receptor needed for successful entry and subsequent infection of cells by HIV-1. Truncation of the protein through mutation, vis-à-vis CCR5∆32, prevents HIV-1 from entering the cell, thus infection cannot be established. Transplantation of stem cells from a donor homozygous for CCR5∆32 results in the recipient possessing cells resistant to HIV-1.

(B) Jensen et al. and Hsu et al. both report on two individuals who received stem cell transplantations, albeit via two different methods. Jensen and colleagues report on an HIV-1 cure in a 53-year-old male who received a CCR5∆32 allogeneic stem cell transplant, similar to the previous two successful cure study subjects.⁵ Hsu and colleagues instead are the first to demonstrate an HIV-1 cure in a mixed-race woman via CCR5∆32 cord blood transplant.⁶ Figure created using BioRender.

More recently, Jensen et al. extended these findings by describing the ‘‘Duesseldorf patient’’ (Figure 1B).⁵ This person, a 53-year-old HIV-1-infected male with acute myeloid leukemia (AML), received an HSCT from a donor homozygous for CCR5∆32 in 2013. After successfully engrafting and developing a complete remission of leukemia, he interrupted treatment in 2018 and has maintained undetectable plasma viral loads for 4 years since ART interruption. Laboratory testing, using tissue culture and PCR-based assays, failed to identify replication-competent HIV-1 in 213 million cells (peripheral blood mononuclear cells [PBMCs], CD4⁺ T cells, and memory T cells, collectively), although trace quantities of the virus with unclear clinical significance were detected in tissues, which was unable to lead to recrudescence. Cellular HIV-1 immune responses waned following the treatment interruption, a result that supports clearance of HIV-1.

In an additional case report by Hsu et al., the first successful HIV-1 cure in a mixed-race woman (the ‘‘New York patient’’) diagnosed with AML is described (Figure 1B).⁶ Due to the lack of donor hematopoietic stem cells from a CCR5∆32-homozygous person, this individual received a haploidentical cord blood transplant from a CCR5∆32 homozygous infant, followed by antiretroviral treatment interruption 37 months later; at the time of the report, this person remained in drug-free control of HIV-1 for 18 continuous months. Using a standard tissue culture viral outgrowth assay, the investigators failed to detect replication-competent HIV-1 in 74.5 million CD4 T cells from this study participant, although trace HIV-1 DNA (1.1 copies/million PBMCs) was detected shortly after treatment interruption, without a concomitant rebound.

The work by Hsu et al. has significant implications for persons living with HIV-1 with mixed ancestry. A key concern with transplantation is matching for human leukocyte antigens (HLAs), with HLA disparity between donor and recipient frequently leading to post-transplant complications such as graft-versus-host disease. In persons of mixed ancestry, finding an HLA-matched donor who simultaneously is homozygous for the CCR5∆32 deletion can be very difficult because homozygous carriers of this gene variant are less frequent in individuals of non-White ancestry.⁴ Cord blood samples might be helpful in these situations, as they contain fewer alloreactive T cells and therefore require markedly reduced stringency in HLA matching compared to adult unrelated hematopoietic stem cells; in fact, use of cord blood has substantially extended allograft access to racial and ethnic minorities. Therefore, the use of cord blood donor cells with homozygous CCR5∆32 alleles might represent a viable approach for treatment of mixed-race individuals living with HIV-1 and requiring hematopoietic stem cell transplants for hematologic malignancies. That being said, cord blood transplants are not without drawbacks: because of the more limited availability of hematopoietic stem cells from cord blood, engraftment is frequently delayed, resulting in prolonged neutropenia, protracted hematologic recovery, and increased risks for transplantation-associated complications.⁷

While these specific cases appear to be successful with no remission of infection, several instances have been reported of HSCTs and haplo-cord transplant with CCR5∆32 cells that failed, with recipients succumbing to a relapse in their hematologic malignancy, graft rejection, graft-versus-host disease, or infectious disease complications.^6–8 Moreover, rebound with CXCR4-tropic viruses has been reported in an individual who received a CCR5∆32 HSCT,⁹ and shifting of HIV-1 tropism in the setting of CCR5∆32 hematopoietic stem cells transplants generally remains a concern. Finally, recent work demonstrated low-level viral rebound with CCR5-tropic HIV-1 in one person following an HSCT from a donor homozygous for CCR5∆32 (Paul Rubinstein et al., 2023, CROI, abstract), reflecting further limitations and uncertainties of this approach.

Together, these studies demonstrate great progress in our ability to cure HIV-1 in persons with hematologic malignancies. With advances in high-throughput screening for donors homozygous for CCR5∆32, these types of transplants may develop into a more routine standard of care for people living with HIV-1 and hematologic malignancies. Indeed, a recent press release from the City of Hope hospital in Los Angeles reports a further individual possibly cured of HIV-1 via HSCT. That said, it is important to emphasize that HSCT is not suitable for treating HIV-1 in persons without concomitant malignant diseases; finding a cure for HIV-1 in such persons through nontoxic, broadly applicable interventions represents the ongoing focus of intense research.