Radically different
Antiretroviral therapy (ART) has enabled most people living with HIV to live long and healthy lives. However, a small portion of people experience detectable traces of the virus, known as nonsuppressible viremia (NSV), despite strict adherence to long-term treatment regimens and the absence of symptoms. The results of a study headed by researchers at Johns Hopkins University School of Medicine now suggest that most cases of NSV are explained by defective and noninfectious copies of the virus.
The study, which involved more than 50 people, found that while traces of HIV-1 RNA can persist in blood after optimal therapy, cases of non-suppressible viremia are driven by HIV-1 RNA with defects in a piece of the RNA known as 5’-leader. The team developed a digital PCR (dPCR) assay, CLAWS (Capturing 5′ Leader Anomalies Without Sequencing), that distinguishes intact from defective 5′L RNA.
“From a clinical perspective, this is important because people with HIV are taught that the absolute goal of their medication is to achieve undetectable viral load, and they worry,” said Francesco R. Simonetti, MBChBD, PhD, an assistant professor of medicine in the Division of Infectious Diseases at Johns Hopkins University School of Medicine. The new findings, said Simonetti and his team, should provide relief to many people living with HIV who fear a viral rebound or who are concerned about transmitting the virus to partners despite taking effective treatment.
Simonetti is senior and corresponding author of the team’s report in Nature Communications (“5′ leader defects drive persistent HIV-1 viremia on long-term ART”), in which they stated, “These findings identify 5′L-defective genomes as the predominant driver of NSV and establish CLAWS as a practical tool for monitoring viremia in clinical and cure-related settings.”Modern antiretroviral therapies, which date back to 1996, prevent HIV from infecting new populations of immune system cells, but aren’t able to retroactively prevent previously infected cells from releasing HIV viral particles. Since those cells usually represent a small portion of infected cells after a person is on stable therapy, most people with HIV (PWH) who take antiretroviral therapies are able to bring their viral loads to clinically undetectable levels in their blood.
However, in some cases, which are estimated to occur less than 1% of the time, people may experience clinically detectable levels after taking long-term antiretroviral drug therapy. “Traces of HIV-1 RNA can persist in plasma despite long-term suppressive antiretroviral therapy (ART), the authors stated. This could happen years later, or, in less frequent cases, they may have never achieved undetectable levels. “The sources of NSV remain poorly defined, in part due to limited tools to characterize plasma HIV-1 RNA,” the team continued. “NSV raises concerns for virologic failure, transmission, and immune activation, complicates ART management, causing anxiety and ultimately affecting the quality of life of PWH.”
For the newly reported study, the investigators examined blood samples from 52 people living with HIV who had detectable loads of the virus despite taking long-term antiretroviral drug therapy. These samples, which were assessed from 32 people and compared to an additional 20 samples, were collected between 2021 and 2025. The majority of participants were white men, between ages 58 and 68, and received care in the United States, Canada, and Denmark. The researchers found that most detectable forms of the virus, around 95%, were due to defective copies, and most defects were due to mutations or deletions in the 5’-leader region of HIV-1 RNA. This region is known to orchestrate the production of copies of the virus, but in this case, the defects prevented the generation of infectious virus.
“In 31 participants from the original NSV cohort and an additional 20 participants from the validation cohort, RNA transcribed from defective proviruses accounted for a median of 95% of plasma HIV-1 RNA, firmly establishing their central role in persistent viremia,” the investigators wrote in summary.
The study offers evidence that clinicians can now study the virus in blood plasma and confirm if clinically detectable levels are due to defective copies released from one or a few T-cell clones, said Simonetti. If so, he added, this could eliminate the need for extra medications and could prevent related complications. It could also help people living with HIV have access to surgeries or other procedures, such as hip or knee replacements or organ transplants, and participate in clinical studies if they know they have HIV under control.
“We know that these defective proviruses cannot infect new cells, but they are still clinically relevant,” said Simonetti. “Think of how many extra visits, extra drugs, extra costs, and tests they’ve been causing. It’s also clear from the new study that, over time on treatment, intact proviruses that make virus are pruned away, while defective ones escape the immune system,” he said. “Now we want to understand these differences in immune recognition to uncover HIV’s vulnerabilities.”
Similar to using a liquid biopsy to detect cancer mutations in DNA, the CLAWS assay developed by the researchers uses advanced technology to identify detectable viral loads that are due to defective copies. The method is cost-effective and can be broadly used in HIV clinics and research settings.
In their paper, the authors wrote in conclusion, “In summary, our results establish 5’L-defective proviruses as the major source of NSV and introduce CLAWS as a practical tool for dissecting persistent viremia. Beyond clarifying mechanisms of HIV-1 persistence, CLAWS provides immediate translational utility for clinical monitoring and HIV-1 cure research.”
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A cup of coffee can mean many things: a daily part of our routine, a moment of calm, a midday boost. But zoom in past the steam, past the roasted aromatics, down to the caffeine molecule itself, and a different story emerges. At the Texas A&M Health Institute of Biosciences and Technology, researchers have turned this everyday stimulant into something far more unexpected: a molecular “pause button” for engineered cells.
In a study published in the Journal of the American Chemical Society (JACS), the team unveiled CODS, a caffeine‑operated dissociation system built using AI‑guided de novo protein design. The paper, “AI‑Guided De Novo Design of a Caffeine‑Induced Protein Dissociation System,” describes how the group reprogrammed “an existing caffeine-responsive chemically induced proximity (CIP) module into a ligand-dependent dissociation system.”
“AI is changing how we design biology,” said senior author Yubin Zhou, MD, PhD. “Instead of relying only on protein parts that already exist in nature, we can now design new mini proteins with specific behaviors. Here, we used AI to help turn caffeine into a precise trigger for controlling engineered cells.”
The CODS system pairs a caffeine‑binding protein with a synthetic mini‑binder designed using the BindCraft platform. In the absence of caffeine, the two components stay locked together. Add caffeine, and the complex snaps apart, releasing the binder and shutting down the attached cellular function. As Tianlu Wang, PhD, a postdoctoral fellow in the Zhou lab, put it, “Many genetically-encoded molecular tools act like accelerators. CODS gives us something closer to a brake or pause button.”
The team demonstrated CODS across several biological contexts. In engineered gene circuits, caffeine addition sharply reduced transcriptional activity. In a rewired pyroptosis pathway, caffeine triggered inflammatory cell death by freeing the active domain of gasdermin D. And in perhaps the most translational example, CODS served as a conditional deactivator for CAR T cells, temporarily dampening their activity without destroying the therapeutic cells.
“Powerful therapies need powerful control,” Zhou said. “By combining AI‑designed proteins, high‑performance computing, and familiar small molecules, we are building a new language for communicating with engineered cells.”
The design process itself leaned heavily on computation. Graduate student Brendan McKee led the AI‑guided binder design and molecular modeling, while Tatsuki Nonomura spearheaded the molecular engineering and live‑cell validation. The Texas A&M High Performance Research Computing service provided the infrastructure needed to run large‑scale simulations. “High‑performance computing was essential for this project,” Zhou noted. “It helped us move from a conceptual idea to a functional molecular switch much faster.”
Although caffeine is not a therapeutic molecule, its safety and familiarity make it an appealing control signal. As Zhou emphasized, “Coffee will not replace medicine. But caffeine can help us imagine medicines that are more controllable, more responsive, and safer for patients.” The researchers’ next steps include further testing in therapeutic cells, animal models, and disease-relevant settings before moving toward clinical use.
CODS now joins a growing toolkit of AI‑designed molecular switches, offering a blueprint for future systems responsive to other safe, accessible molecules. As programmable cell therapies advance, the ability to modulate them with something as simple as caffeine may prove unexpectedly powerful.
The authors report that a patent application covering the CODS platform has been filed by Texas A&M University, with Y.Z., T.N., B.M., and T.W. listed as inventors (U.S. Provisional Patent Application No. 64/022,078).
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AstraZeneca’s investigational GLP-1 pill showed promise in mid-stage obesity and diabetes studies, but it may still be too early to determine how it stacks up against oral treatments already on the market.
In one Phase 2 trial of people with obesity, called VISTA, those on the highest dose of the drug, called elecoglipron, lost 11.2% of their weight after 36 weeks, when looking at all patients regardless of discontinuations, according to data presented Monday at the annual meeting of the American Diabetes Association and published in the Lancet. (Eli Lilly’s pill Foundayo led to the same rate of weight loss in a Phase 3 study that lasted twice as long, but it’s hard to compare across trials in different phases.)
In a separate Phase 2 trial in people with diabetes, called SOLSTICE, patients on the highest dose saw up to a 1.74 percentage-point decrease in a measure of blood sugar called A1C after 26 weeks. The study, also published in the Lancet, enrolled people taking oral Ozempic open-label as a comparator group, and they experienced a smaller A1C decrease of 1.32 percentage points.
Institut Pasteur is launching ACT-CHIK (Accelerating Clinical Trials for CHIKungunya Vaccine in Africa), a four-year research project funded by the Global Health EDCTP3 Joint Undertaking under the European Union’s Horizon Europe program that aims to advance clinical trials and prepare for the manufacturing of a chikungunya vaccine in Africa.
With €15.3 million in EU funding, ACT-CHIK will advance the development of MV-CHIK—a measles-virus-based chikungunya vaccine originally developed at Institut Pasteur—through a large-scale Phase Ib/III clinical trial in four African countries, while preparing for technology transfer to an African vaccine manufacturer.
“Chikungunya remains a neglected disease in Africa despite its growing burden. ACT-CHIK represents a unique opportunity to generate critical clinical data in the populations that need this vaccine most, while simultaneously building the foundation for regional vaccine manufacturing on the continent,” notes Sotiris Missailidis, DPhil, ACT-CHIK project coordinator at Institut Pasteur.
Chikungunya is a mosquito-borne viral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes. It causes debilitating symptoms, including high fever, severe joint pain that can persist for months or even years, headache, rash, and fatigue. Over the past two decades, the number of chikungunya cases reported across Africa has risen sharply. Yet, the disease remains largely underdiagnosed and under-reported, particularly in regions where multiple arboviruses and malaria co-circulate. Climate change is further expanding the range of mosquito vectors, increasing the risk of outbreaks across the globe, and most notably in Africa.
Although chikungunya vaccines have recently become available, their use remains limited largely among travelers, with cost and access constraints hindering their deployment in endemic regions. The MV-CHIK candidate is designed to be accessible to populations in endemic areas and aims to support local production. This positioning will address a major gap in equitable access to vaccination and to strengthen outbreak preparedness in regions where the need is greatest.
The MV-CHIK vaccine is a live-attenuated, recombinant vaccine using the well-established measles virus Schwarz vaccine strain as a vector—a platform technology originally developed at the Institut Pasteur in Paris. Six Phase I and II clinical trials conducted in Europe, the United States, and Puerto Rico, including approximately 600 adult participants in total, have demonstrated satisfactory safety, tolerability, and immunogenicity profiles.
Building on these results, ACT-CHIK will conduct a Phase Ib/III multicenter, international clinical trial to evaluate the safety and immunogenicity of MV-CHIK in adults, adolescents, and children living in Rwanda, Kenya, Nigeria, and Senegal. By enrolling 940 participants across both endemic and non-endemic areas, the trial will generate essential data to advance the clinical development plan for African populations, including younger age groups.
Beyond clinical evaluation, the project has a strategic manufacturing dimension. ACT-CHIK will conduct comprehensive due diligence, gap analysis, and prepare for the technology transfer of the MV-CHIK vaccine manufacturing process to the Institut Pasteur de Dakar (IPD), Africa’s only WHO-prequalified vaccine manufacturer. Fundação Oswaldo Cruz (Fiocruz) in Brazil, a fellow member of the Pasteur Network, will prepare the clinical trial materials and contribute its extensive vaccine manufacturing expertise to the technology transfer process.
The project will also develop a regulatory pathway for the licensure of the MV-CHIK vaccine in Africa through engagement with national regulatory authorities and the World Health Organization prequalification teams, to obtain prequalification.
ACT-CHIK directly supports Africa’s ambition—as set by the African Union—to produce 60% of the continent’s vaccine needs locally by 2040, and is aligned with the European Union’s Team Europe Initiative on Manufacturing and Access to Vaccines (TEI MAV+).
“ACT-CHIK will mobilize the full breadth of expertise at Institut Pasteur de Dakar: from clinical trials to cutting-edge virology and immunology laboratories, from vaccine research to manufacturing expertise. This project embodies our vision: an Africa that develops, evaluates, and produces its own vaccines—for the populations that need them most,” notes Ibrahima Socé Fall, PhD, CEO of Institut Pasteur de Dakar.
The ACT-CHIK consortium brings together seven partner institutions with complementary expertise:
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Researchers have demonstrated that key restorative functions of sleep can be triggered in localized regions of the awake brain, providing new insights into why sleep is essential for learning and memory.
The NIH-funded study, led by investigators at the University of Wisconsin–Madison, showed that artificially inducing sleep-like patterns of neural activity in specific brain regions of sleep-deprived mice restored memory performance and reduced the need for subsequent sleep in those areas. The findings, published in Nature Neuroscience, suggest that the characteristic activity patterns of non-rapid eye movement (NREM) sleep, not simply reduced brain activity, play a central role in maintaining healthy neural circuits.
The work offers a new window into the biological mechanisms that allow sleep to refresh the brain and may eventually inform non-invasive approaches to combat cognitive impairment associated with sleep loss.
Researchers have long shown that sleep is essential for memory formation and learning, but the precise mechanisms underlying these benefits remain incompletely understood.
During NREM sleep, which accounts for approximately 80% of adult sleep, the brain undergoes extensive reorganization. Connections between neurons, known as synapses, are selectively strengthened, maintained, or weakened. This process is thought to secure important memories while preventing neural networks from becoming overloaded with information accumulated during wakefulness.
Previous studies from the laboratory of senior author Chiara Cirelli, MD, PhD, found that sleep-deprived animals and humans occasionally exhibit brief episodes of localized slow-wave activity, the characteristic electrical pattern of NREM sleep, even while remaining awake. These observations raised the possibility that small portions of the brain might temporarily enter a sleep-like state independently of the rest of the brain.
The question remained whether a more sustained version of this phenomenon could reproduce some of sleep’s restorative effects.
To investigate, the researchers developed an experimental system that allowed them to generate sleep-like activity in targeted regions of the brain without causing the animals to fall asleep.
Using genetically modified mice equipped with light-sensitive neural circuits, the team delivered rhythmic pulses of light that produced alternating periods of neuronal activation and silence. These oscillations closely resembled the “on-off” firing patterns observed during NREM sleep.
The stimulation was applied to one hemisphere of the brain in sleep-deprived mice for 30-minute periods while the animals remained awake and responsive to their environment.
Cirelli compared the phenomenon to a strategy observed in nature.
“What we’re essentially doing is forcing sleep in a local region of the brain,” she said. “While that part is solidifying memories and restoring learning capacity, other parts stay aware/vigilant and connected to environment.”
She noted that dolphins exhibit a related behavior, sleeping with one cerebral hemisphere at a time while the other remains awake.
The researchers found that brain regions receiving the sleep-like stimulation subsequently displayed lower levels of slow-wave activity during natural sleep.
Slow-wave activity is widely considered a measure of sleep pressure, the biological drive to sleep that accumulates during wakefulness. Reduced slow-wave activity suggested that the stimulated brain regions had already undergone part of the restorative process normally achieved during sleep.
The results challenged a longstanding hypothesis that sleep’s benefits primarily arise from globally reducing neuronal firing rates to relieve fatigue.
Instead, the study found that restoration depended specifically on the rhythmic alternation between active and inactive states characteristic of NREM sleep. Simply suppressing neuronal activity was insufficient.
The findings suggest that the temporal structure of neural activity during sleep may be more important than the overall amount of activity.
To determine whether the induced sleep-like activity produced meaningful behavioral benefits, the researchers evaluated the animals using a tactile memory task that normally depends on adequate sleep.
Sleep-deprived mice typically perform poorly on this type of test, reflecting impaired memory consolidation and reduced learning capacity.
However, sleep-deprived mice that received bilateral stimulation of sensory and motor brain regions performed nearly as well as animals that had not been deprived of sleep. In contrast, sleep-deprived mice that did not receive stimulation showed significantly impaired performance.
These results suggest that localized sleep-like activity can compensate for at least some of the cognitive deficits caused by sleep loss.
The work provides new support for the concept that sleep serves as a form of neural recalibration.
Throughout wakefulness, experiences continuously modify synaptic connections, increasing the strength and number of neural links. Without a mechanism to rebalance these networks, the brain could eventually lose efficiency, consume excessive energy, and struggle to encode new information.
NREM sleep appears to provide a structured period during which these connections are selectively refined. The current study indicates that the characteristic slow oscillations of NREM sleep may be the critical driver of this process.
By recreating these oscillations in isolated brain regions, researchers were able to trigger aspects of the reset mechanism without requiring the entire brain to enter sleep.
Although the experiments relied on invasive genetic and optical techniques that are not currently applicable to humans, the investigators believe the findings may inform future therapeutic strategies.
The next step will be determining whether similar effects can be achieved using non-invasive approaches such as transcranial brain stimulation, which can modulate neural activity through the scalp.
If successful, such methods could eventually help mitigate cognitive deficits associated with sleep deprivation, shift work, aging, or neurological disorders.
“This research further decodes why we sleep and how we learn, which brings us a step closer to understanding how to better prevent and treat cognitive decline,” said Amy Bany Adams, PhD, acting director of the NIH’s National Institute of Neurological Disorders and Stroke.
While a replacement for sleep remains firmly out of reach, the study reveals that some of sleep’s most important restorative processes may be far more localized, and potentially more controllable, than previously appreciated.
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A study led by researchers at the University of Texas at El Paso (UTEP) has found that people with type 2 diabetes or obesity who were prescribed GLP-1 receptor agonists (GLP-1 RAs) had substantially lower odds of developing alcohol, opioid, nicotine, and cocaine use disorders compared with similar individuals who were not taking the medications. The research, published in the journal Frontiers in Psychiatry, used health data from more than 142,000 patients from the All of Us Research Program and adds to a growing body of evidence indicating that GLP-1 medications may have an influence on dopamine signaling and other neural pathways that drive cravings not just for food but other substances.
“Our findings add to growing evidence that GLP-1 medications may influence more than appetite and blood sugar regulation,” said lead author Tadesse Abegaz, PhD, an assistant professor in the School of Pharmacy, University of Texas at El Paso. “These medications appear to affect brain pathways involved in reward and craving, which could help explain the lower rates of substance use disorders observed in our study.”
Substance use disorders are a significant public health challenge contributing to illness, premature death, and higher healthcare costs. While current treatment methods that combine medications and behavioral therapy can be effective, relapse rates remain high, often exceeding 50% within the first year after treatment, suggesting a need for additional ways to treat this disease.
An emerging candidate for this are GLP-1 receptor agonists such as semaglutide and liraglutide. Developed to treat type 2 diabetes and obesity, these drugs have drawn attention because GLP-1 receptors are found not only in areas involved in metabolic regulation but also in brain regions associated with reward and reinforcement.
“Animal studies have demonstrated that GLP-1 RAs reduce the self-administration of alcohol, opioid, nicotine, and cocaine effects [that] are believed to be mediated through interactions with the mesolimbic dopamine system,” the researchers wrote. Small human studies and observational analyses have also suggested reductions in substance cravings, relapse rates, and alcohol-related hospitalizations among some patients receiving GLP-1 therapies.
The El Paso investigators said they initiated their research to move beyond smaller studies because “the real-world impact of GLP-1 RA on multiple co-occurrence of SUD (substance use disorder) has not been systematically investigated.”
To address this gap, the team conducted a retrospective nested case-control study using data from the NIH’s All of Us Research Program. The study examined individuals with type 2 diabetes or obesity and identified cases involving new diagnoses of alcohol use disorder, opioid use disorder, nicotine use disorder, or cocaine use disorder. These individuals were compared with matched control participants who had diabetes or obesity but no documented history of substance use disorders.
Analyses of these data showed consistent associations across all categories studied. GLP-1 receptor agonist use was associated with a 74% reduction in the odds of alcohol use disorder, a 69% reduction in the odds of opioid use disorder, a 68% reduction in the odds of nicotine use disorder, and a 75% reduction in the odds of cocaine use disorder. The researchers also reported 75% lower odds of any substance use disorder among GLP-1 users compared with non-users.
“Exposure to GLP-1 RAs was consistently associated with significantly reduced odds of SUD cases,” the researchers wrote. “These findings suggest that GLP-1 RAs may exert behavioral-modifying effects that extend beyond glycemic control and weight loss.”
The researchers noted that their research was observational and does not establish cause and effect. “We do not support prescribing these medications for addiction treatment at this time,” said senior author Gabriel Frietze, PhD, an assistant professor of pharmaceutical sciences at UTEP. “Because this was an observational study in a specific clinical population, randomized clinical trials are needed before GLP-1 medications can be recommended for treating addiction.”
The team believes the findings could help guide future approaches to addressing substance use-related health issues by identifying biological pathways that may be targeted therapeutically. The authors noted that mechanisms potentially involved include modulation of dopamine release, suppression of neuroinflammation, and attenuation of stress-related neural circuits.
“Our next goal is to conduct prospective research that follows individuals initiating GLP-1 therapy over time,” Abegaz said. “We aim to evaluate whether changes in the substance use behaviors occur after treatment begins and whether these changes related to improvements in mental health and quality of life. Ultimately, this work will help inform whether GLP-1 medications could become part of future treatment strategies for substance use disorders.”
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