In a groundbreaking advancement that challenges longstanding paradigms in HIV research, scientists have reported an extraordinary case of durable HIV remission achieved without the classic CCR5 Δ32 homozygous mutation previously deemed critical for curing the virus. The study, recently published in Nature by Gaebler, Kor, Allers, and colleagues, unveils the compelling story of a male patient who sustained virus-free status for over six years post allogeneic stem cell transplantation (allo-SCT) – despite receiving stem cells carrying only a heterozygous CCR5 wild-type/Δ32 genotype.
HIV cure remains the holy grail of modern medicine, an elusive endpoint attained in only six known instances worldwide among the approximately 88 million individuals infected since the epidemic began. Historically, the documented cures – most famously, the “Berlin patient” – have involved allogeneic stem cell transplantation as treatment for hematological malignancies, utilizing donors with the rare homozygous CCR5 Δ32 mutation. This mutation renders the CCR5 receptor nonfunctional, effectively barring HIV entry into CD4+ T cells, and has long served as the cornerstone of mechanisms explaining antiretroviral therapy (ART)-free remission.
However, emerging evidence now points towards more complex and diverse underpinnings of viral eradication beyond CCR5 Δ32-mediated resistance. In this landmark case, the patient, who initially presented with acute myeloid leukemia and HIV infection, underwent allo-SCT using hematopoietic stem cells from an unrelated HLA-matched donor harboring a heterozygous CCR5 genotype. Contrary to prior beliefs, the donor’s stem cells retained a functionally active CCR5 receptor, indicating traditional CCR5-based resistance was insufficient to explain the patient’s unprecedented viral remission.
Remarkably, after three years of continued ART post-transplantation, the patient discontinued all antiretroviral drugs. Follow-up examinations over a span exceeding six years revealed continuously undetectable plasma HIV RNA levels, without any indications of viral rebound. This durable remission without pharmacological intervention pushes the frontiers of what is considered achievable and challenges researchers to rethink the fundamental mechanisms governing viral persistence and clearance.
Extensive analysis of the viral reservoir – the latent pool of HIV-infected cells that persist despite ART – provided further insights into this phenomenon. Prior to transplantation, intact proviral HIV DNA was detected, confirming a substantial viral reservoir. Yet post-transplant, advanced assays failed to identify any replication-competent virus in both peripheral blood and intestinal tissues. These results attest to a profound reduction, if not complete elimination, of the latent HIV reservoir.
Beyond the quantifiable absence of infectious virus, immune profiling revealed a concurrent waning or total loss of HIV-specific antibody and T cell responses. This immunological quiescence aligns with the hypothesis that the virus was no longer actively replicating or stimulating the host immune system. Intriguingly, the study also highlights elevated antibody-dependent cellular cytotoxicity (ADCC) activity present at the time of transplantation, suggesting that immune-mediated clearance mechanisms may have synergized with transplantation-induced factors to purge infected cells.
This case disrupts the long-held dogma that homozygous CCR5 Δ32 mutation is an indispensable requirement for HIV cure. Instead, it underscores the paramount importance of achieving comprehensive reductions in the viral reservoir and mobilizing effective immune effector pathways. These insights open new vistas for therapeutic research aimed at replicating such durable HIV remission in a broader population of infected individuals.
From a clinical perspective, these findings fuel optimism about the potential of refining allo-SCT protocols or developing analogous therapies capable of drastically shrinking or eradicating viral reservoirs without relying exclusively on donor genetic resistance. It also shifts attention towards harnessing and enhancing innate and adaptive immune functions, including ADCC, as complementary agents in cure strategies.
The implications extend into the realm of cure research design, emphasizing the need for deeper mechanistic studies dissecting how post-transplant microenvironments, donor-recipient cellular interactions, and immune modulation collectively contribute to viral elimination. Moreover, this case provides a valuable template for investigating CCR5-independent pathways, potentially broadening the scope of curative interventions beyond the confines of rare donor genotypes.
As the global health community strives to confront the HIV pandemic, which continues to impact millions globally, such unprecedented findings catalyze renewed hope for achieving lasting remission and eventual eradication. They galvanize a multifaceted approach that goes beyond genetics alone, integrating immunology, reservoir biology, and innovative transplant methodologies.
In summary, the sustained HIV-1 remission observed in this heterozygous CCR5Δ32 allo-SCT recipient fundamentally alters prevailing perspectives on HIV cure mechanisms. By demonstrating that durable viral control and reservoir elimination can occur in the absence of homozygous CCR5-mediated resistance, this discovery challenges researchers to rethink and expand therapeutic frontiers. Continued exploration into the underlying biology will be crucial for translating these insights into scalable, safe, and effective HIV cure strategies in the near future.
Subject of Research: HIV remission mechanisms following allogeneic stem cell transplantation with heterozygous CCR5Δ32 genotype.
Article Title: Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation.
Article References:
Gaebler, C., Kor, S., Allers, K. et al. Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation. Nature (2025). https://doi.org/10.1038/s41586-025-09893-0
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