New hope for cure of HIV-infected patients

Le résumé fourni par la source

Human immunodeficiency virus (HIV) infection remains a major global health threat due to a lack of efficient prophylactic vaccines and curative treatments. In 2022, there were 39 million people living with HIV (PLWH) worldwide and 1.3 million new infections. Since the HIV epidemic began more than 40 years ago, at least 40 million people have died from acquired immunodeficiency syndrome (AIDS). An important part of antiretroviral therapy (ART) is the use of drugs that target different processes of the HIV life cycle that occur within CD4+ T cells, such as viral replication and integration. Ideally, ART significantly reduces the plasma viral load to an undetectable level and stops the progression of HIV infection to AIDS. Thus, ART is crucial in extending the lives of HIV-infected individuals, and it has saved millions of lives. However, ART does not cure HIV infection because it cannot eliminate virions that reside within in vivo HIV reservoirs, which are mainly found in latently infected CD4+ T cells.[1,2] Furthermore, due to the longevity of memory CD4+ T cells, HIV can persist as an integrated provirus within a host for decades, only to be detected by the immune system when reactivated.[3] Another challenge associated with ART is that HIV can rapidly rebound from its reservoirs if ART is discontinued. Consequently, lifelong ART is necessary. Additionally, there are other significant limitations associated with ART, including insufficient drug supply in some regions and the need for a robust healthcare infrastructure to provide treatment and monitor ongoing viral suppression, which is not available in many resource-limited settings. The success of ART is also impacted by the development of drug resistance and side effects, as well as the social stigma faced by PLWH. Therefore, there is an urgent need to develop a cure for HIV infection. Despite efforts to develop a cure for HIV infection, particularly after the case of the “Berlin Patient” was reported, only a few cases of stable cure have been recorded worldwide, and each involved a patient who received a stem cell transplant. In one case, that of the “Geneva patient,” the donor had wild-type (WT) CCR5. In most other cases, the donor was a homozygous carrier of the CCR5 Δ32 mutation; that is, they had a 32-base pair deletion in the CCR5 gene (CCR5 Δ32/Δ32). CCR5 is a β-chemokine receptor and a major coreceptor for HIV on CD4+ T cells. The CCR5 Δ32 mutation leads to the absence of CCR5 on the cell surface, which renders cells naturally resistant to the CCR5-tropic HIV variants.[4] Approximately 10% of Northern Caucasians carry the CCR5 Δ32 mutation; however, only about 1% have a homozygous allele.[5] Notably, the seventh cured patient underwent an allogeneic hematopoietic stem cell transplant with cells from a donor with a heterozygous CCR5 WT/Δ32 allele and stopped ART approximately three years after the transplant, and their HIV remission has lasted for over five years. Following the successful treatment of the Berlin Patient in 2008, the Berlin University Medical Organization used a similar but slightly modified approach to treat a second patient who had both acute myeloid leukemia (AML) and AIDS with a hematopoietic stem cell transplant (HSCT). According to a report presented at the 25th International AIDS Conference,[6] the 60-year-old man from Germany was diagnosed with HIV infection in 2009 and later with AML. In 2015, he received an HSCT. In this case, the treatment team could only find a human leukocyte antigen (HLA)-matched (10/10) unrelated donor with a homozygous CCR5 Δ32 mutation due to the rarity of the homozygous mutation. Notably, the transplantation resulted in complete donor chimerism and AML remission. The patient’s acute graft-versus-host disease (GVHD; grade I) was limited to the skin and was treated with topical steroids. The patient stopped receiving ART in September 2018, and his viral load remains undetectable (<20 copies/mL). For nearly six years, the research team has repeatedly tested the patient’s peripheral blood, duodenum, and ileum for HIV DNA and has found no signs of the virus. His CD4+ T-cell count has returned to a normal level. During the follow-up period, the patient’s HIV-specific antibody levels have decreased, and no HIV-specific T-cell responses have been detected. All the data suggest that the patient’s HIV reservoir has disappeared or is fully controlled, and he is considered cured of HIV infection. This case further demonstrates that the cure of HIV infection via an allogeneic HSCT may not be reliant on the use of homozygous CCR5 Δ32/Δ32 donors. The successful treatment of the second Berlin patient provides new information that can be used in the development of a cure for HIV infection. First, the patient received a graft with the heterozygous CCR5 WT/Δ32 mutation rather than the homozygous CCR5 Δ32/Δ32 mutation, which meant that the reconstituted immune cells remained susceptible to HIV infection, albeit to a lesser degree than those containing WT CCR5. This suggests that the patient’s GVHD played a critical role in the clearance of any existing virions before the immune cells were reconstituted. In a recent retrospective study of 30 HIV-positive patients with hematologic malignancies who received transplants, mathematical modeling results suggested that allogeneic immunity mediated by donor cells was the primary mechanism responsible for viral reservoir depletion following substantial reservoir reduction during conditioning chemotherapy before an allogeneic HSCT.[7] Additionally, we have developed a safe and well-tolerated HLA-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients that has resulted in improved clinical symptoms and immune restoration.[8,9] Notably, we have also observed that allogeneic transplantation has an inhibitory effect on viral replication.[8] These findings underscore the need for further research into the mechanisms by which grafts inhibit viral activity. Second, the patient was diagnosed with HIV infection in 2009 and began ART in 2015. The intensity of the patient’s chemotherapy was reduced prior to the transplant, and the GVHD was not severe. These observations suggest that the threshold for curing HIV via an HSCT might not be as high as previously assumed, which positively impacts the scalability of this approach as a strategy for curing HIV. Given the low prevalence of the CCR5 Δ32 mutation among Asians, researchers in China are focusing on editing T-cell genes, and significant strides have been made in this area. For instance, Chen et al. transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 and acute lymphoblastic leukemia.[10] Moreover, CCR5-modified autologous CD4+ T cells are being investigated in preclinical and clinical studies as potential components of a cure for HIV infection. However, autologous cells lack GVHD-dependent antiviral effects, and further clinical data are needed to evaluate their efficacy. Despite these promising advancements, the journey toward a definitive cure for HIV infection remains challenging. In terms of HSCT-based strategies, donor cells containing the CCR5 Δ32 mutation are not readily available, and there are inherent uncertainties and risks. For example, the factors critical for success may be complex and unclear, there is risk associated with performing pre-transplant conditioning, and post-transplant immune rejection and other complications (e.g., infections) may occur. Funding This work was supported by the National Key R&D Program of China (2023YFC2308300, 2023YFC2308302). Author Contributions Yan-Mei Jiao and Chao Zhang search literature and organize the manuscript. Fu-Sheng Wang provide guidance and revise the manuscript. All authors discussed on the manuscript and approved the final manuscript. Conflicts of Interest None. Editor note: Fu-Sheng Wang and Yan-Mei Jiao are the edit

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