Sara Gianella Weibel, de la UC San Diego, es la encargada de abrir la sesión plenaria de nuestro Congreso el martes, 26 de noviembre. En su intervención nos mostrará los principales resultados de su proyecto ‘Last Gift Study’ y lo aprendido sobre el VIH gracias al estudio de cadáveres.
What are the main lessons learned about HIV from people who are at the end of their lives?
The Last Gift Study is a truly transformative project, and it continues to be one of my favorite studies for many reasons. End-of-life research offers a unique opportunity to analyze tissues that are otherwise inaccessible in living individuals, such as the brain, lymph nodes, gut, and bone marrow. Through this study, we have gained profound insights into how HIV persists in various reservoirs despite effective antiretroviral therapy (ART).
One of the key advantages of this study is the use of rapid autopsy procedures, which enable us to obtain high-quality tissues, viable cells, and intact proteins and nucleic acids. This level of preservation is critical for conducting detailed and accurate analyses that would otherwise be impossible.
Our findings have revealed the complexity and dynamism of latent viral reservoirs. For the first time, we demonstrated the presence of a replication-competent reservoir in the human brain. Furthermore, we observed that reservoirs are not static; proviruses can migrate across tissues and across the blood brain barrier, even during ART, likely carried by immune cells. Importantly, our research suggests that the mechanisms of viral persistence in the brain may differ significantly from those in peripheral tissues. This highlights the need for tailored strategies to target and eliminate reservoirs across different compartments of the body.
Beyond the scientific discoveries, the lessons we’ve learned and we continue to learn from our study participants are equally impactful. Their altruism, selflessness, and dedication to giving back to their communities inspire us every day. Each participant’s story is unique, reminding us of the humanity behind our work and the profound impact their contributions have on advancing science and improving lives.
What are the main differences found about HIV compared to other people who are not at the end of their lives?
The differences in HIV among individuals at the end of their lives compared to those who are not can be profound, both scientifically and personally. One of the most striking aspects of people at the end of life is their deep desire to give back and leave a lasting legacy for their community. Many participants in studies like the Last Gift are long-term survivors who have endured significant loss and pain throughout their lives. For them, contributing to scientific advancement at the end of their life is incredibly meaningful and offers a sense of purpose.
From a scientific perspective, the diseases they experience and the dying process itself can influence the HIV reservoirs. For example, the physical stressors and systemic changes that occur near death might alter reservoir dynamics in ways we are only beginning to understand. However, the Last Gift Study stands out because each participant is followed very closely until the time of death, providing an unmatched depth of information. This includes detailed clinical, virological, and immunological data, as well as personal histories, which give a much richer context than most other autopsy cohorts.
Human studies are inherently complex due to the unique nature of each individual, and this variability can make it challenging to draw broad conclusions. Yet, this is also what makes such studies so fascinating. They allow us to explore how diverse life histories, disease courses, and end-of-life conditions shape HIV reservoirs, offering insights that could not be gained in more controlled but less personalized studies. The Last Gift Study bridges the gap between the individual’s story and the broader scientific narrative, making it a unique and invaluable resource
And how can they help us in the search for better treatments and even a possible functional cure?
Data from the Last Gift study are essential for advancing HIV cure research, as they reveal critical insights into the virus’s behavior in tissues, where the majority of the reservoir resides. Most cure studies primarily focus on blood samples, yet this provides only a partial picture of HIV persistence. Tissue reservoirs, such as those in the brain, lymph nodes, and gut, often harbor distinct viral populations and unique mechanisms of latency that may not be reflected in blood.
For example, in one study, we observed viral populations in the brain with unique predicted resistance patterns to neutralizing antibodies—highlighting the brain as a potential sanctuary for resistant virus. Additionally, our preliminary data suggest that the epigenetic mechanisms governing latency in the brain differ from those in blood. These differences could influence how the virus responds to latency-reversing agents or other cure-directed therapies, underscoring the need to tailor interventions to specific tissues.
Without addressing these tissue-specific reservoirs and mechanisms, cure strategies risk leaving behind resistant or latent virus that could undermine long-term remission. The Last Gift’s focus on analyzing tissues postmortem provides an unprecedented opportunity to understand these hidden aspects of HIV persistence, paving the way for more effective and comprehensive cure strategies.
What other research projects are you working on?
A promising future step in the Last Gift study involves collaborating with cohort participants and community members to explore end-of-life interventions aimed at understanding the penetration of therapeutic drugs into deep tissues. This research is critical because most HIV cure studies focus on the virus in blood, while the vast majority of the viral reservoir resides in tissues such as the brain, gut, and lymph nodes.
By studying how drugs distribute and penetrate these tissues at the end of life, we can gain invaluable insights into their effectiveness against the latent virus hiding in these compartments. For instance, some therapeutic agents may exhibit limited penetration into certain tissues, such as the brain, due to barriers like the blood-brain barrier. This could allow viral reservoirs in these regions to persist, even in individuals undergoing otherwise effective treatments.
Interventions at the end of life provide a unique opportunity to directly assess drug distribution and efficacy in eradicating HIV from these critical reservoirs. This research not only has the potential to inform the design of more effective cure strategies but also demonstrates the profound partnership between researchers, participants, and communities in advancing the science of HIV cures.