CROI 2025 Abstract eBook

Abstract eBook

Invited Session

expression after integration. Further studies showed that tethering to cellular chromatin binding proteins contributed to targeting. Recent studies in people with HIV who effectively control virus show that distributions may be enriched in regions where the virus is poorly expressed due to aggressive selection by CD8+ T cells. These results have been recapitulated in various cell culture and animal models, allowing detailed mechanistic analysis. Studies of integration targeting also inform monitoring of human gene therapy, where insertional mutagenesis by gene transfer vectors is a concern. Recent studies suggest that HIV and retroviral vectors can carry out insertional mutagenesis in humans via four different mechanisms: enhancer insertion, promoter insertion, gene inactivation, and gene activation by mRNA 3’ end substitution. Stepping back, these mechanistic studies provide an overview of how basic research advances treatment of HIV, and contribute to the conceptual foundation for addressing many other disorders. 40+ Years of HIV: What’s Changed, What Hasn’t, What Shouldn’t, What Must Rebecca Denison Woman Organized to Respond to Life-threatening Diseases (WORLD), Berkeley, CA, USA Background: We are gathering in a moment of tremendous challenges and opportunities. We have developed biomedical tools to prevent HIV transmission and support the wellbeing of over 38 million individuals living with HIV, yet a truly healthy world eludes us. Stigma, discrimination, preventable deaths, and inequitable access to resources and health care persist. Human rights that have progressed in some places are under attack in others. Across the U.S., and perhaps the world, we are more connected yet more lonely than ever before. Our greatest achievements in evidence-based science are undermined by misunderstandings and deliberate disinformation. While many young people in the U.S. have never heard of HIV, and many of their parents think “AIDS is over,” the internet offers newly diagnosed people a firehose of information at the expense of their privacy. Meanwhile, their elders — long-term and lifetime survivors — bear the weight of trauma, gratitude, and persistence in a world unprepared to meet the needs of people aging with HIV. The challenges we face call for creativity, collaboration, and courage. Please join 42-year HIV survivor Rebecca Denison — Bay Area writer, founder of WORLD, co-founder of ICW, and clinical research participant since 1985 — as she reflects on lessons from the past, challenges in the present, and opportunities for the future. When Science Alone is Not Enough: The Intersection of Drug Use, Public Health, and Policy Adeeba Kamarulzaman Monash University Malaysia, Kuala Lumpur, Malaysia Background: From the beginning of the pandemic, people who inject drugs (PWID) were identified as a key population at significant risk of HIV infection. However, despite evidence of the effectiveness of harm reduction, many countries failed to respond adequately or in a timely manner. Embedded in prohibition and punitive approaches, Malaysia’s initial resistance to harm reduction led to a large, concentrated epidemic amongst PWID. Although now more widely adopted, to date very few countries have achieved targets for opioid agonist therapy or met the recommended number of needles and syringes distributed per year. With less than 1% of total HIV spending allocated to programs for PWID globally, it is no surprise that PWID continue to be left behind in access to prevention and treatment programs. Far from its intended aim of protecting individuals and society from the harm of drug use, punitive drug laws and prohibition continue to result in diseases, deaths from drug overdoses, prison overcrowding, violence and a cycle of poverty. Drug use is often seen through a moral lens, with users stigmatized as criminals or morally deficient rather than individuals in need of help. This stigma makes it challenging to build public support for harm-reduction policies and programmes. Many fear that alternative approaches, such as legalization or decriminalization, could lead to unintended consequences, including increased drug use or addiction, despite evidence from countries like Portugal demonstrating otherwise. The “War on Drugs” relied on fear-based narratives and racialized rhetoric that continue to shape public opinion. This is compounded by global treaties, such as

the 1961 Single Convention on Narcotic Drugs, which tie nations to prohibitionist policies and make reform on an international scale more difficult. Despite these challenges, there is a growing recognition of the failure of prohibition and increasing momentum for reform. The success of alternative approaches, such as decriminalization and harm reduction, highlights the potential for treating drug use as a public health issue rather than a criminal one. However, overcoming the entrenched political, economic, and cultural barriers to change requires sustained effort, evidence-based policymaking, and a shift in public perception toward compassion and practicality over punishment. By leveraging evidence, building partnerships, and engaging in public discourse, the scientific community can challenge outdated drug policies and push for reforms grounded in science, equity, and compassion. Background: Antiretroviral therapy (ART) has transformed HIV-1 infection from a fatal disease into a manageable chronic condition. However, longitudinal studies reveal that the decay rate of the HIV-1 reservoir is so slow that ART alone cannot eliminate the reservoir within the lifetime of people living with HIV-1 (PLWH). This underscores the urgent need for safe and scalable strategies to achieve an HIV-1 cure. Most HIV-1 cure strategies fall into two main categories: (1) approaches aimed at eradicating or inactivating the reservoir and (2) approaches designed to induce immune-mediated control of the virus. Hematopoietic stem cell transplantation (HSCT) has demonstrated the potential to completely eradicate the HIV-1 reservoir, as seen in case reports of PLWH receiving HSCT for hematologic conditions. However, due to its inherent risks, HSCT is not a feasible cure strategy for otherwise healthy individuals. Consequently, most research has shifted toward strategies focused on immune-mediated control of HIV-1. Cytotoxic CD8+ T cells are strongly associated with spontaneous HIV-1 control, making the enhancement of CD8+ T cell immunity a promising avenue for clearing infected cells and achieving long-term viral suppression. Despite these prospects, therapeutic HIV-1 vaccines have so far failed to produce the desired results in clinical trials. Nevertheless, a range of other compounds - both those specifically designed for HIV-1 cure and repurposed drugs from fields such as oncology and hematology - have been investigated for their potential to impact HIV-1 persistence. While many of these interventions have not succeeded in significantly reducing the reservoir or inducing robust adaptive immune responses, recent trials have reported encouraging outcomes, with some individuals achieving partial or complete long-term control of HIV-1 after discontinuing ART. These findings raise the possibility that a functional cure for HIV-1 is achievable. In this talk, I will provide an overview of the most promising therapeutic strategies in the pursuit of an HIV-1 cure, including the use of broadly neutralizing antibodies. I will also discuss key populations that may have a higher likelihood of achieving a cure and address the critical barriers that remain in developing effective interventions. Additionally, I will review findings from in-depth studies of the biological mechanisms underlying sustained HIV-1 suppression in individuals who maintain control for years after stopping ART. Background: This "state of the pandemic plenary will review the current status of the global pandemic; interrogate recent available data on HIV incidence from placebo arms of RCT and PURPOSE trials; review data on mortality; elucidate the challenges of primary prevention in high HIV burden and lower HIV burden populations; explore the challenges of late diagnoses and advanced HIV disease; and suggest ways forward for an invigorated response using new prevention tools which could achieve epidemic control. The key themes and messages, supported by current evidence are that: • We did not meet the UNAIDS 2025 targets on HIV incidence or mortality and are not on track for 2030 • HIV incidence remains too high to achieve pandemic control • The social determinants of HIV incidence remain formidable barriers to prevention, treatment, and care • Both MSM and Trans communities globally, and women and girls in SSA, remain at high lifetime acquisition probability in multiple countries The Global HIV/AIDS Pandemic: Where Are We Now? Chris Beyrer Duke Global Health Institute, Durham, NC, USA HIV Cure: A Translational Research Perspective Ole Søgaard Aarhus University, Aarhus, Denmark

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CROI 2025