The findings shed light on the requirements for a successful cure and the stepwise clearance of the virus from the body. This research marks a significant advancement in understanding HIV eradication and paves the way for the development of a more accessible cure for the estimated 38 million people worldwide living with HIV.
The Power of Allogeneic Immunity
Allogeneic immunity, the immune response mounted by donor stem cells, emerged as a major driver of HIV reservoir clearance. The study, published in the journal Immunity, employed MHC-matched alloHSCT in SIV-positive Mauritian cynomolgus macaques (MCMs) that were receiving antiretroviral therapy (ART). The researchers demonstrated that allogeneic immunity played a pivotal role in eliminating the latent viral reservoir. The clearance process initiated in the peripheral blood, followed by the peripheral lymph nodes, and finally the mesenteric lymph nodes connected to the gastrointestinal tract.
While allogeneic immunity alone showed promising results in extirpating the viral reservoir, it proved insufficient in cases where protection of engrafting cells was not provided by CCR5 deficiency. Despite full ART suppression, the CCR5-tropic virus managed to spread to donor CD4+ T cells. This observation highlighted the importance of donor cells lacking the CCR5 receptor in preventing HIV infection, thus emphasizing the significance of both allogeneic immunity and CCR5 deficiency in achieving a successful HIV cure.
Understanding the Order of HIV Clearance
The study also unraveled the stepwise fashion in which HIV is cleared from the body. The researchers meticulously documented the sequence of HIV clearance, starting with the elimination of the virus from the peripheral blood circulating in the limbs. Subsequently, HIV was cleared from lymph nodes in the limbs, followed by clearance from lymph nodes in the abdomen. This orderly clearance pattern provides valuable insights for evaluating the effectiveness of potential HIV cures and offers an explanation for cases where patients initially appeared cured but later experienced viral resurgence.
The journey toward a cure: Past and Present
The concept of using stem cell transplantation as a potential cure for HIV was first realized in the famous case of the “Berlin patient” in 2009. This individual, diagnosed with both HIV and acute myeloid leukemia, received a stem cell transplant from a donor possessing a mutated CCR5 gene. The mutation made it difficult for the virus to infect cells, resulting in the eradication of HIV from the patient’s body. Since then, four more individuals have been cured of HIV using similar approaches.
The current study focuses on Mauritian cynomolgus macaques, which have shown successful outcomes in receiving stem cell transplants. Four of the study’s eight subjects received transplants from HIV-negative donors, while the remaining four served as controls without transplants. Two of the transplant recipients were ultimately cured of HIV following successful treatment for graft-versus-host disease, a common complication associated with stem cell transplantation. Remarkably, these two animals remain HIV-free and in good health four years after transplantation, underscoring the potential of this approach.
Unveiling the Mechanisms Behind the Cure
While confirming the efficacy of stem cell transplantation in curing nonhuman primates infected with HIV, the researchers aimed to unravel the underlying mechanisms responsible for the successful outcomes. By analyzing samples from the subjects, they identified two essential factors contributing to the cure.
Firstly, the transplanted donor stem cells exhibited a potent immune response against the recipient’s HIV-infected cells. These transplanted cells recognized the infected cells as foreign invaders and initiated an attack, akin to the graft-versus-leukemia effect observed in cancer treatment. This immune-mediated elimination of HIV-infected cells played a crucial role in reducing the viral reservoir and paving the way for a cure.
Secondly, the researchers discovered that preventing the virus from utilizing the C-C chemokine receptor 5 (CCR5) was equally vital for achieving a cure. Donor cells lacking the CCR5 receptor provided a protective barrier against HIV infection. Normally, HIV relies on the CCR5 receptor to enter target cells and establish infection. However, in the presence of CCR5-deficient donor cells, the virus encountered a significant hurdle, hindering its ability to infect and propagate within the host.
The researchers demonstrated the interplay between these two factors in the context of alloHSCT. While allogeneic immunity played a central role in reservoir clearance, the protective effect of CCR5 deficiency was necessary to prevent viral spread to donor CD4+ T cells. This finding highlights the significance of combining allogeneic immunity and CCR5 deficiency in achieving a comprehensive and durable HIV cure.
The stepwise clearance of HIV observed in the study provides further insights into the dynamics of viral eradication. The researchers observed a sequential pattern of HIV clearance, starting with the elimination of the virus from the peripheral blood circulating in the limbs. Subsequently, clearance occurred in the lymph nodes of the limbs and eventually extended to the lymph nodes in the abdomen. This systematic clearance pattern informs clinicians and researchers about specific sites to monitor when evaluating the effectiveness of potential HIV cures and may help explain instances of viral resurgence observed in some patients.
The Power of Stem Cell Transplants
The study, published in the journal Immunity, focuses on the successful cure of Simian Immunodeficiency Virus (SIV), the monkey form of HIV, in two nonhuman primates after receiving a stem cell transplant. Stem cell transplants have previously been proven effective in curing HIV, with five documented cases in humans to date. This research aims to unravel the underlying mechanisms responsible for these cures, leading to the potential development of a widespread cure for HIV.
Two Essential Factors for a Cure
The study identified two crucial factors that must coincide for a cure to occur through alloHSCT. First, the transplanted donor stem cells must eliminate the recipient’s HIV-infected cells by recognizing them as foreign invaders and attacking them. This process mirrors the graft-versus-leukemia effect observed in cancer treatment, where transplanted cells target and eliminate cancerous cells. Second, the virus must be prevented from using the C-C chemokine receptor 5 (CCR5) to infect the donor cells. Donor cells lacking the CCR5 receptor provide a protective barrier against HIV, as the virus typically relies on this receptor for entry into cells.
Stepwise Clearance of HIV
The researchers meticulously traced the clearance of HIV from the body, observing a sequential pattern. Initially, the virus was eliminated from the peripheral blood circulating in the limbs. Subsequently, it was cleared from lymph nodes in the limbs and then from lymph nodes in the abdomen, specifically the mesenteric lymph nodes draining the gastrointestinal tract. This stepwise clearance pattern provides valuable insights for evaluating the effectiveness of potential HIV cures and highlights the importance of analyzing blood samples from both peripheral veins and lymph nodes.
Combining Allogeneic Immunity and CCR5 Deficiency
While allogeneic immunity alone proved effective in extirpating the latent viral reservoir in some cases, it was insufficient in others. In those instances, protection against viral spread to donor CD4+ T cells was provided by CCR5 deficiency, preventing the virus from infecting donor cells despite full antiretroviral therapy (ART) suppression. The study underscores the individual contributions of allogeneic immunity and CCR5 deficiency to achieving a cure for HIV and supports the exploration of targets for alloimmunity-based curative strategies independent of stem cell transplantation.
Implications for a Widespread Cure
The findings of this study hold promising implications for the development of a more accessible and widely applicable cure for HIV. Researchers aim to streamline the cure process, ideally through a single injection, to eliminate the need for a stem cell transplant. By understanding the intricate mechanisms involved in alloHSCT-mediated HIV cure, scientists can advance their efforts to replicate and optimize this treatment approach, bringing hope to millions affected by HIV worldwide.
Looking to the Future
These groundbreaking findings pave the way for further investigations into the immune responses and specific immune cells involved in achieving a cure for HIV. The researchers plan to delve deeper into understanding the precise mechanisms and molecules targeted by the immune system in order to refine curative strategies and make them more accessible to a larger population. The ultimate goal is to develop a cure for HIV that can be administered through a single injection, eliminating the need for complex and invasive stem cell transplantation procedures.
Furthermore, these findings provide hope for individuals living with HIV. By uncovering the crucial factors necessary for a cure, researchers are one step closer to developing transformative treatments that can eradicate HIV and improve the quality of life for millions of people worldwide.
Conclusion
The stepwise clearance pattern of HIV observed in the study provides valuable information for evaluating potential HIV cures and understanding disease progression and persistence. The study’s findings bring researchers closer to developing a widespread cure for HIV, with the ultimate goal of delivering it through a single injection, eliminating the need for a stem cell transplant.
The study builds upon previous cases of HIV cure through stem cell transplants, starting with the famous “Berlin patient” in 2009. This patient, who had both HIV and acute myeloid leukemia, received a stem cell transplant from a donor with a CCR5 mutation, which confers resistance to HIV infection. Since then, four more individuals have been cured using similar methods. The current research focuses on Mauritian cynomolgus macaques, a nonhuman primate species that can successfully receive stem cell transplants.
Among the eight subjects in the study, four received transplants from HIV-negative donors, while the other four served as controls without transplants. Two of the transplant recipients were cured of HIV after successfully treating graft-versus-host disease, a common complication of stem cell transplants. Notably, these two animals remain alive and HIV-free even four years after transplantation, thanks to exceptional care and support provided by the researchers and clinicians.
The study investigated the mechanisms behind the HIV cure by evaluating samples from the subjects. It identified two essential ways in which the transplants contributed to HIV clearance. First, the transplanted donor stem cells recognized and attacked the recipient’s HIV-infected cells as foreign invaders, similar to the graft-versus-leukemia effect in cancer treatment.
This process played a critical role in eliminating the virus. Second, in cases where the virus was not cleared, HIV managed to infect the transplanted donor cells during their attack on HIV-infected cells. This observation highlighted the necessity of preventing HIV from using the CCR5 receptor to infect donor cells for a cure to occur.
Additionally, the study observed a stepwise clearance of HIV from the body. The virus was first eradicated from the peripheral blood circulating in the limbs, followed by clearance from lymph nodes in the limbs and eventually lymph nodes in the abdomen. This sequential clearance pattern provides valuable guidance for evaluating the efficacy of potential HIV cures and helps explain why some patients initially appeared cured but later experienced viral resurgence.
Moving forward, the researchers plan to delve deeper into the immune responses of the two nonhuman primates cured of HIV. They aim to identify specific immune cells and molecules involved in the clearance process. By gaining a comprehensive understanding of the immune system’s role in the cure, they hope to develop targeted curative strategies that can be applied independently of stem cell transplantation.
The results of this research have significant implications for the development of a cure for HIV. By elucidating the mechanisms underlying HIV clearance through alloHSCT, scientists are making progress towards making the cure accessible to a larger population. With further research and refinement, the goal of a widespread HIV cure may be within reach, providing hope for millions of individuals affected by this global health challenge.
Funding for this study was provided by the National Institutes of Health (NIH) and the Foundation for AIDS Research (amfAR), among others. OHSU ensures transparency and manages potential conflicts of interest regarding the researchers’ financial interests in relevant companies. All animal research at OHSU undergoes rigorous ethical review and approval by the Institutional Animal Care and Use Committee (IACUC) to ensure the welfare of research subjects and the researchers involved.
reference link “Allogeneic immunity clears latent virus following allogenic stem cell transplantation in SIV-infected antiretroviral therapy-suppressed macaques” by Jonah Sacha et al. Immunity
