Microscopic view of immune cells interacting with HIV virions and stem cells, representing HIV reservoir depletion and immune reconstitution after stem cell transplant.

Unlocking HIV Cure: New Insights into Reservoir Depletion

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Lena Voss in Health & Wellness August 2025 • 5 min read.

"Can Allo-HSCT with Wild-Type Donor Cells Pave the Way for HIV Remission?"


The quest to cure HIV has seen a monumental breakthrough with the case of Timothy Ray Brown, who was cured of both HIV and cancer through an allogeneic hematopoietic stem cell transplant (allo-HSCT). While the exact mechanisms remain a subject of intense investigation, Brown's case ignited a wave of research focused on replicating this success.

A pivotal hypothesis emerged: that the transplant of cells from a donor with a mutated CCR5 coreceptor—rendering the cells resistant to HIV—played a crucial role. This success, once deemed impossible, spurred efforts to explore similar and alternative strategies.

Recent advancements have allowed for the maintenance of HIV replication suppression through antiretroviral therapy (ART) without hindering the engraftment of allogeneic donor stem cells. This has paved the way for evaluating potential HIV cures in patients undergoing allo-HSCT with CCR5 wild-type donor cells while under ART's protective cover. Remarkably, studies have observed reservoir depletion to levels previously unseen with other interventions, though delayed viral rebound after ART cessation has been noted. This reinforces the complexity of achieving a complete cure and highlights the knowledge gaps that still exist.

The Allo-HSCT Advantage: Depleting HIV Reservoirs

Microscopic view of immune cells interacting with HIV virions and stem cells, representing HIV reservoir depletion and immune reconstitution after stem cell transplant.

Salgado and colleagues have contributed significantly to this field by studying a large cohort of HIV-infected patients undergoing allo-HSCT with CCR5 wild-type donor cells for hematologic diseases. Their research delves into the question of how allo-HSCT, even with wild-type donor cells, can lead to such radical depletion of latent HIV reservoirs.

Using highly sensitive assays, the researchers found no traces of latent HIV after allo-HSCT in their study participants. While ART was not interrupted to confirm the absence of residual, replication-competent HIV, the findings suggest a substantial impact on the viral reservoir. The study identifies several factors potentially contributing to this profound depletion:

  • Pretransplant conditioning (immunosuppression): The intensity of immunosuppression before transplant may play a role.
  • Posttransplant immune activation: Immune responses following the transplant could stimulate the reactivation of latent HIV genomes, making them susceptible to clearance.
  • Alloreactivity of donor immune cells: Donor immune cells might target and eliminate HIV-infected recipient cells, a phenomenon termed a "graft-versus-HIV-reservoir" effect.
The researchers observed that a graft-versus-HIV-reservoir effect, a positive consequence of the graft-versus-host effect, correlated with reductions in HIV reservoirs. Conversely, less reservoir depletion was associated with the use of cord blood stem cells and antithymocyte globulin (ATG) for conditioning, potentially due to the greater immunosuppression and immaturity of cord blood stem cells diminishing the graft-versus-HIV-reservoir effect. These correlations provide a foundation for future research aimed at more precisely defining the mechanisms behind the reservoir reductions seen with allo-HSCT.

Immunity's Role and Future Directions

The importance of immunity in controlling HIV is further supported by studies examining other approaches to HIV remission and cure. These studies highlight the critical contribution of autologous immune responses in delaying viral rebound after ART is stopped. Research into the characteristics of these "rebound-delaying" autologous immune responses is essential to understanding how they slow active virus replication and potentially clear reservoir cells.

The findings from allo-HSCT studies, along with other research showing the potential for delayed viral rebound in specific patient populations, suggest that some individuals may have reliably reduced reservoirs. This could make them ideal candidates for clinical trials evaluating strategies for cure or sustained remission in the context of ART withdrawal.

Analytic ART interruption, carefully designed to identify the immune characteristics that distinguish patients with typical viral rebound dynamics from those with delayed rebound, is crucial. Ultimately, a deeper understanding of the interplay between allogeneic and autologous immune responses may unlock new strategies for achieving sustained HIV remission, applicable to a broader range of individuals living with ART-suppressed HIV.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

Everything You Need To Know

1

What is allogeneic hematopoietic stem cell transplant (allo-HSCT), and how does it relate to HIV?

Allogeneic hematopoietic stem cell transplant (allo-HSCT) involves replacing a patient's immune system with cells from a donor. In the context described, this approach is explored as a potential pathway to an HIV cure by profoundly depleting HIV reservoirs. This is a significant advancement because it moves beyond solely managing the disease through antiretroviral therapy (ART) and aims to eliminate the virus from the body. The success of allo-HSCT hinges on factors like the donor's cell type and the immune responses following the transplant, creating a 'graft-versus-HIV-reservoir' effect.

2

What is the significance of the CCR5 coreceptor in the context of HIV treatment?

The CCR5 coreceptor is a protein on the surface of immune cells that HIV uses to enter and infect them. A mutated CCR5 coreceptor makes cells resistant to HIV infection. In the context of allo-HSCT, using donor cells with a mutated CCR5 coreceptor has been a strategy to prevent HIV from infecting new cells after the transplant. However, the research discussed highlights that even with CCR5 wild-type donor cells, significant reservoir depletion can occur, broadening the scope of potential treatment strategies.

3

Why are HIV reservoirs important, and how does allogeneic hematopoietic stem cell transplant (allo-HSCT) impact them?

HIV reservoirs are hidden pools of the virus that persist in the body, even when HIV replication is suppressed by antiretroviral therapy (ART). They are a major barrier to curing HIV because the virus can reactivate from these reservoirs once ART is stopped. In the study, the depletion of these reservoirs, observed after allogeneic hematopoietic stem cell transplant (allo-HSCT), is crucial because it suggests a potential for long-term remission or even a cure by eliminating the virus's hiding places.

4

How does the immune system contribute to the success of allogeneic hematopoietic stem cell transplant (allo-HSCT) in treating HIV?

Immune responses after allogeneic hematopoietic stem cell transplant (allo-HSCT) play a pivotal role in depleting HIV reservoirs. Post-transplant immune activation can stimulate the reactivation of latent HIV genomes, making them susceptible to clearance. The donor immune cells can also target and eliminate HIV-infected recipient cells, creating a graft-versus-HIV-reservoir effect. The nature of these immune responses, and the use of immunosuppressants before the transplant, influences the effectiveness of allo-HSCT in reducing the viral reservoir.

5

What is the role of antiretroviral therapy (ART) in the context of allo-HSCT for HIV?

The use of antiretroviral therapy (ART) is a critical element in managing HIV and is used with allo-HSCT. ART helps suppress HIV replication, preventing new infections and allowing the immune system to recover. Studies have been conducted that maintain HIV replication suppression through ART without hindering the engraftment of allogeneic donor stem cells. This strategy allows researchers to evaluate potential HIV cures in patients undergoing allo-HSCT. Delayed viral rebound after ART cessation underscores the complexity of achieving a complete cure and indicates the need for further research.

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