A drug that blocks danger signals that can lead to harmful inflammation could help reduce COVID-19 lung damage, a new study from NIAID scientists and colleagues has found. Scientists from NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, and the University of Utah completed the project, published online in JCI Insights.

Though they completed the study in laboratory mice modified to model COVID-19 in people, the scientists think their findings are important enough to pursue further studies of the drug, FPS-ZM1, to determine dosing and timing strategies for possible human clinical trials. FPS-ZM1 is an immune modulatory therapeutic – the drug is designed to prevent a specific immune system response from occurring. The investigational therapy has been evaluated in preclinical studies to treat conditions such as diabetes, lung injury and stroke. In their study, the scientists used FPS-ZM1 to block the “receptor for advanced glycation end products” (RAGE), which senses danger signals and can generate inflammation and coagulation known to damage the lungs of COVID-19 patients. 

Therapeutic treatment with FPS-ZM1 during the study improved survival in mice infected with SARS-CoV-2, the virus that causes COVID-19. Further, FPS-ZM1 specifically reduced damage to the lung vasculature, an important system for circulating blood through the lungs that becomes damaged during SARS-CoV-2 infection. FPS-ZM1 also has shown in other rodent studies that it can protect against injury in disease models of brain injury, sepsis, asthma, diabetes, acute lung injury and ischemic/reperfusion (organ damage due to blood flow).

The study also identified two distinct phases of COVID-19 disease development in the mice. The scientists want to further explore those phases as potential guides for treatment strategies. For example, FPS-ZM1 limited specific types of inflammation and tissue damage, so it would likely be most effective if administered during the intermediate to later stages of SARS-CoV-2 infection, whereas antiviral treatment may be most effective when given early following infection.

Reference: F Jessop, et al. Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection. JCI Insights DOI: https://doi.org/10.1172/jci.insight.155896. (2022).
 

COVID-19 Respiratory Treatment Effective in Encephalitis Study

Molnupiravir Reduced Viral Brain Disease in Mice

NIAID research into finding broad uses for existing drug treatments has a potential new success story: Molnupiravir, a relatively new antiviral developed to treat respiratory diseases – such as COVID-19 – reduced brain swelling in study mice infected with a pathogen dangerous to children, La Crosse virus (LACV).

The new study, from NIAID scientists and colleagues at the University of North Carolina and Emory University, is published in PLOS Pathogens. LACV, which is spread by mosquitos, can cause brain inflammation in children. LACV was first isolated in the early 1960s near La Crosse, Wisconsin. Since then, LACV encephalitis cases have been found in more than 20 states, mostly in the basins of the Mississippi and Ohio rivers and throughout the Appalachian Mountains.

Most LACV infections in people are mild, but the virus sometimes – particularly in children – enters the brain, infects neurons and causes disease that can result in learning and memory difficulties, paralysis, seizures and death. Between 30 and 90 cases of severe LACV – those that affect the central nervous system (CNS) – are reported each year, though the Centers for Disease Control and Prevention believes many mild cases occur but are not diagnosed.

The study used a new strategy to test three antiviral drugs – N4-Hydroxycytidine (NHC, the active metabolite of the prodrug molnupiravir), ribavirin and favipiravir– for treatment against LACV infection. The scientists chose LACV because it broadly represents several RNA viruses that cause disease in the CNS, including Jamestown Canyon and Cache Valley viruses – which also were part of the study – and rabies, polio, West Nile, Nipah and several other viruses not part of the study.

The three antiviral drugs were tested in a cell culture system to examine an antiviral strategy called lethal mutagenesis. This approach increases the number of errors in the viral genome that RNA viruses make when they replicate, weakening the resulting viruses. By incorporating the drug, more errors are induced in the viral genome and more weakened viruses emerge, providing the host an opportunity to recover.

Ribavirin and favipiravir used in cell treatment studies did not produce potent enough results to justify testing in mice. The NHC prodrug molnupiravir, however, was used in two different mouse study models. Oral treatment with molnupiravir reduced brain disease in mice by 32% when LACV infection was started by an injection in the abdomen, and by 23% when the infection was started in the nose, offering easy access to the brain.

Also noteworthy: The researchers tested NHC against LACV and found it effective in the cell and mouse models, as well as in cell models using Jamestown Canyon and Cache Valley viruses. This showed that the drug treatment strategy could be successful against viruses related to LACV and supports the idea that this strategy could be used against a broader group of encephalitic RNA viruses.

The researchers say more study is needed to see how these drugs counter RNA viruses, particularly to determine whether injecting the drug directly into cerebrospinal fluid would provide better results and possibly reduce adverse side effects.

Reference:

D Ojha et al. N⁴-Hydroxycytidine/Molnupiravir Inhibits RNA Virus-Induced Encephalitis by Producing Less Fit Mutated Viruses. PLOS Pathogens DOI: 10.1371/journal.ppat.1012574 (2024).

In the early 1980s, scientists identified clumps of abnormal, misfolded prion protein in mammals as the cause of brain-wasting diseases, now called prion diseases. Since that time, they have struggled to answer: What does a normal prion protein do?

The answer, they believe, could help lead them to develop treatments and disease-prevention measures against human prion diseases, such as Creutzfeldt-Jakob disease, fatal familial insomnia and kuru, as well as animal prion diseases, such as scrapie in sheep and chronic wasting disease in cervids.

Now, a new study published in iScience from NIAID scientists at Rocky Mountain Laboratories in Hamilton, Montana, and colleagues provides details of how prion protein functions in the retina of mouse eyes, helping them respond to light.

The scientists used mice specially bred without prion protein to compare to wild mice with natural prion protein. Prior studies have suggested that prion protein may have a role in how nerves transmit signals to other nerves at specialized junctions, known as neural synapses. So, knowing that prion protein exists naturally in the eye, the researchers examined mouse retina for a specific neural synapse role.

A key tool the researchers used involved measuring the electroretinographic (ERG) responses – the amount of time it took for the retina in mice to respond to a flash of light. Remember as a kid in school learning about rods and cones in the eye and how they convert light signals to help the brain understand vision? The same is true in mice.

Compared to the wild mice with prion protein, the scientists observed deficiencies in ERG responses for mice without prion protein. The deficiencies affected the normal function of the rods and cones. And – using the ERG data and neural synapse information – they found that the deficiencies originated in the portion of the retina where natural prion protein was most highly concentrated.

Though additional study is needed, the researchers believe the prion protein may act like scaffolding to help cells and elements of the eye, such as rods and cones, to stabilize neural synapses. And they believe prion protein must be present for rods and cones to function normally.

The research team hopes these findings help colleagues who study prion diseases better understand what might occur in humans when natural forms of prion protein are therapeutically removed. New treatment strategies for prion diseases focus on using drugs that remove natural prion protein to eliminate the potential for misfolding and clumping. But researchers do not know whether that could result in unwanted outcomes, such as possibly affecting vision. These findings also could extend to other protein-related neurodegenerative diseases, such as Alzheimer’s (amyloid beta protein) and Parkinson’s diseases (alpha synuclein protein).

Scientists from Duke University and the McLaughlin Research Institute in Great Falls, Montana, collaborated on the study.

Reference: J Striebel, et al. The prion protein is required for normal responses to light stimuli by photoreceptors and bipolar cells. iScience DOI: 10.1016/j.isci.2024.110954 (2024).

Fourteen vaginal bacterial species and the presence of a protein that promotes inflammation were associated with increased odds of HIV acquisition in a study of more than 500 cisgender women in African countries with high HIV incidence. The study was the largest to date to prospectively analyze the relationship between both the vaginal microbiome and vaginal tissue inflammation and the likelihood of acquiring HIV among cisgender women in this population. The NIAID-sponsored research was published in The Journal of Infectious Diseases.

Research is limited regarding the potential impacts of vaginal bacteria and inflammatory markers on HIV acquisition. Only one previous study has characterized both factors in women before they had HIV to investigate their odds of acquiring the virus, but the number of HIV acquisition events in that study was low, potentially limiting their ability to detect associations.

To increase understanding of these issues, researchers analyzed vaginal swab samples from 586 cisgender women participating a large biomedical HIV prevention clinical trial in South Africa, Uganda and Zimbabwe, and compared the bacterial and inflammatory profiles of samples from 150 participants who acquired HIV during the study with the samples of 436 participants who did not. The team identified 14 bacterial species associated with HIV acquisition and noted that participants whose samples contained most or all of those bacteria had the highest odds of acquiring HIV, while the presence of none or few of the identified bacteria was associated with the lowest odds of HIV acquisition. They similarly identified six inflammatory cytokines and chemokines—proteins that communicate with other cells to prompt the body to fight infections through inflammatory processes—associated with HIV acquisition, and identified the highest odds of HIV acquisition in participants whose samples contained all six of those proteins. Furthermore, they identified a single chemokine called interferon gamma-induced protein 10 associated with the highest odds of HIV acquisition out of the six.

These results suggest that strategies to reduce concentrations of the 14 identified bacterial species and inflammatory proteins could help prevent HIV acquisition, according to the authors. They also recommended that additional studies be conducted to understand the mechanisms by which these factors contribute to biological susceptibility to HIV.

Reference: Srinivasan, S et al. Vaginal Bacteria and Proinflammatory Host Immune Mediators as Biomarkers of HIV Acquisition 3 Risk among African Women. Journal of Infectious Diseases. DOI 10.1093/infdis/jiae406 (2024).

This blog is the second in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

The impact of clinical research is often measured by its outcomes. From trials that provide groundbreaking evidence of efficacy to those stopped early for futility, the end results of clinical trials shape practice and future research priorities. However, years of effort from scientists, study teams and study participants while a trial is underway are sometimes overshadowed by final study outcomes. In this regard, trial implementation requires clinical research sites’ operational excellence for the duration of a study. Access to relevant populations depends on the location of each clinical research site as well as investigators' and clinical care providers’ engagement with the local community and understanding of their needs and preferences. A high-functioning clinical research site anchored in the communities it works in and comprised of cohesive, well-integrated components is essential to producing high-quality outputs. 

Currently, NIAID supports four research networks as part of its HIV clinical research enterprise. The networks are made up of more than 100 clinical research sites, each with local experts, robust research infrastructure, and well-trained, cross-functional staff who maintain standardized procedures and quality controls aligned with their network.

Every seven years, NIAID engages research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of network progress toward short- and long-term scientific goals. This process takes account of knowledge gained since the networks were last funded and identifies essential course corrections based on the latest scientific and public health evidence. Subsequent NIAID HIV research investments build on the conclusions of these discussions. This process includes examining the networks’ infrastructure model, which the Institute updates and refines to stay aligned with its scientific priorities. 

The HIV clinical trials network sites have made tremendous contributions to NIH’s scientific priorities by offering direct access to and consultation with populations most affected by HIV globally, and by delivering high-quality clinical research with strong connections to trusted community outreach platforms. Their approach to community engagement anchors clinical research sites beyond the scope of any individual study, and when possible, aligns scientific questions and study protocols based on local context. 

Since the start of the 2020 research network grant cycle, HIV clinical research sites have enrolled about 93,000 participants across 78 clinical trials in 25 countries. The networks were able to quickly pivot to support NIAID’s emerging infectious disease priority areas, including COVID-19 and mpox. Of the 93,000 participants since 2020, approximately 78,000 were enrolled into COVID-19 clinical trials sponsored by NIAID’s Division of AIDS. 

Clinical trials sites currently operate with a hub-and-spoke model, with each hub providing centralized support to their linked clinical research sites. This model leverages shared resources where possible and practical, and ensures robust oversight to promote high-quality clinical trial operations. Hubs provide infrastructure and services including laboratory, pharmacy, regulatory, data management, and training to support execution of NIAID-sponsored clinical research. 

Future networks will need to maintain core strengths of current models while expanding capacity in areas vital to further scientific progress. These include operations that inform pandemic responses and extending our reach within communities impacted by HIV, including populations historically underrepresented in clinical research. Additionally, there may be opportunities for clinical research sites and other partners to conduct implementation science research based on their capacity and access to relevant populations in the context of specific scientific questions. 

Make seamless progress on established and emerging scientific priorities

Our goals include maintaining the strength and flexibility of our current network model and infrastructure to support established scientific priorities that improve the practice of medicine, including high-impact registrational trials to identify new biomedical interventions and support changes to product labelling. The networks also must remain capable of directing operations to generate evidence on interventions for pandemic responses. 

Engage underserved populations for more representative studies 

Building on its current reach, NIAID and its partners have identified opportunities to expand or strengthen our connections to medically underserved populations affected by HIV, and to increase representation of geographic areas with limited access to current clinical trials sites. We also are seeking clinical research sites with longstanding community relationships and experience conducting randomized clinical trials that include Black gay, bisexual, and other men who have sex with men, transgender people, people who sell sex, people who use drugs, and adolescent girls and young women, as well as populations in African countries with a high HIV prevalence. 

Integrate implementation science within clinical research practice

Implementation science is the scientific study of methods and strategies that facilitate the uptake of evidence-based practice and research into regular use by practitioners and policymakers. As biomedical HIV prevention, treatment, and diagnostic options expand, our scientific questions must expand to address not only whether an intervention works, but how it can be delivered to offer health care choices that people need, want and are able to use. This expanded scientific scope calls for research sites to have a diverse reach and skill sets, including experience and capacity for conducting implementation science research and fostering and maintaining partnerships with organizations that conduct implementation science research on key topics and interventions on which implementers seek stronger evidence.

The research community plays an essential role in shaping NIAID’s scientific direction and research enterprise operations. We want to hear from you. Please share your questions and comments at NextNIAIDHIVNetworks@mail.nih.gov.

About NIAID’s HIV Clinical Trials Networks

The clinical trials networks are supported through grants from NIAID, with co-funding from and scientific partnerships with NIH’s National Institute of Mental Health, National Institute on Drug Abuse, National Institute on Aging, and other NIH institutes and centers. There are four networks—Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.