NIAID Scientists Detail First Structure of a Natural Mammalian Prion

The near-atomic structure of a chronic wasting disease (CWD) prion should help scientists explain how CWD prions spread and become the most naturally infectious of the many mammalian protein aggregation diseases. NIAID scientists revealed the structure in a new study in Acta Neuropathologica. Such detailed knowledge could guide the rational design of vaccines and therapeutics, as well as identify mechanisms that protect humans from CWD pathogens in deer, elk, moose, and reindeer.

Many brain diseases of humans and other mammals involve specific proteins (e.g., prion protein or PrP) gathering into abnormal thread-like structures that grow by sticking to normal versions of the same protein. These threads can also fragment and spread throughout the nervous system and accumulate to deadly levels. For unknown reasons, CWD prions are more naturally contagious than most other protein aggregates and are spreading rampantly among cervid species in North America, Korea and northern Europe. Recalling the bovine spongiform encephalopathy (BSE) or “mad cow disease” epidemic of the mid-1980s and mid-1990s, there are concerns that CWD might similarly be transmissible to humans.

To date, no CWD transmission to humans has been substantiated, and the new CWD structure suggests preliminarily why we might be protected. The structure also reveals multiple differences between CWD and previously determined structures of highly infectious, but experimentally rodent-adapted, PrP-based prions. Differences are even more profound when compared to largely non-transmissible PrP filaments isolated from humans with Gerstmann-Sträussler-Scheinker syndrome, a genetic prion disorder.

PrP-based prion diseases are degenerative, untreatable, and fatal diseases of the central nervous system that occur in people and other mammals. These diseases primarily involve the brain, but also can affect the eyes and other organs. CWD-infected animals shed infectious prions in their feces, urine, and other fluids and body components while alive, and from their carcasses after dying. The prions can remain infectious in the environment for years.

Scientists at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, determined the CWD structure from the brain tissue from a naturally infected white-tailed deer. They isolated the prions and froze them in glass-like ice. Then, using electron microscopy techniques, they developed a 3-D electron density map that indicated the detailed shapes of the protein molecules within the prion structure. This involved taking nearly 80,000 video clips of the sample, magnified 105,000 times the original size, at various orientations. They marked prion filaments in the video clips and collected more than 500,000 overlapping sub-images. They isolated about 7,300 of the highest quality sub-images and then used supercomputers to generate a 3-D density map and a molecular model to fit the map.

Vaccine development is among the many research areas where scientists could use high-resolution prion structures to advance their work. The study authors note that previous attempts to develop vaccines against CWD in cervids failed to be protective, and, at least in one case, had the opposite effect. They speculate that one explanation for adverse vaccine effects could be that antibody binding to the sides, rather than the ends of prion fibril surfaces, promotes fragmentation – creating infectious particles rather destroying them. Thus, a strategy to explore with vaccines and small-molecule inhibitors, they say, is to target the tips of prion structures where binding and conversion of prion protein molecules occurs.

The research team is planning to solve other naturally occurring prion structures, hoping to advance its understanding of the molecular basis of prion transmission and disease.

References:

P Alam, F Hoyt, E Artikis, et al. Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer. Acta Neuropathologica DOI: 10.1007/s00401-024-02813-y (2024).

A Kraus et al. High-resolution structure and strain comparison of infectious mammalian prions. Molecular Cell. DOI: 10.1016/j.molcel.2021.08.011. (2021).

New NIAID-supported science presented at the 2024 HIV Research for Prevention (HIVR4P) conference in Lima, Peru features a breadth of HIV discovery and translational findings and enriches the evidence base on HIV pre-exposure prophylaxis (PrEP) within the context of reproductive health. Select Institute-supported science highlights are summarized below. Full HIVR4P abstracts are posted on the official conference Web site.

Using PrEP Modalities Alongside Contraception and in the First Trimester of Pregnancy

The monthly dapivirine vaginal ring for HIV prevention was safe in cisgender women who used the ring during early pregnancy and then discontinued use as soon as they learned that they were pregnant. In a pre-licensure open-label study of the dapivirine vaginal ring, participants stopped using it if they became pregnant because ring use during pregnancy was beyond the scope of the study. Pregnant study participants remained enrolled after discontinuing the ring and were monitored for safety throughout their pregnancies. An analysis of data from 72 pregnancies found that there were no notable adverse effects among the participants or their infants when the ring was used in early pregnancy. These findings add to the growing evidence that the dapivirine vaginal ring is safe to use throughout pregnancy. Data presented from another study previously confirmed the safety of the ring when participants initiated use during the second trimester and continued to use it until delivery.

An analysis from the Phase 3 study of long-acting injectable cabotegravir (CAB-LA) PrEP in cisgender women found the drug did not interact with long-acting reversible contraceptive (LARC) drugs. A subset of study participants taking the LARCs etonogestrel, medroxyprogesterone acetate or norethindrone provided additional blood samples so that the study team could analyze how taking LARCs together with CAB-LA or oral PrEP with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) could affect the levels of the antiretroviral drugs and contraceptive agents in the body. There were no drug interactions between CAB-LA and any of the LARCs. Interaction between TDF/FTC and LARCs could not be determined because adherence to TDF/FTC was low in the participating cohort. CAB-LA and TDF/FTC were previously shown to be safe for use in pregnancy. 

Early-Stage Findings on HIV Vaccines to Produce HIV Broadly Neutralizing Antibodies

Several studies of germline targeting—a promising HIV vaccine strategy that stimulates the immune system to generate antibodies capable of neutralizing diverse HIV strains—reported results to inform the next stages of vaccine development. Findings in people and animal models showed that several immunogens—molecules used in a vaccine to elicit a specific immune system response—began to prompt immune responses that could generate HIV broadly neutralizing antibodies (bNAbs). In one study of 53 participants without HIV, a vaccine containing a nanoparticle immunogen called 426.mod.core-C4b was safe at multiple dosing levels and appeared to generate B cells capable of producing bNAbs if stimulated further. These findings are informing the development of more advanced HIV vaccine concepts involving the 426.mod.core-C4b immunogen. 

Understanding the HIV Reservoir and HIV Remission Off Antiretroviral Therapy

HIV is difficult to cure because the virus is skilled at “hiding” in the body and can reappear in the blood stream shortly after antiretroviral therapy (ART) is stopped. These hiding places, called reservoirs, are unaffected by ART. NIAID-supported scientists are exploring strategies to clear HIV and its reservoirs from the body or to reduce HIV to levels that can be suppressed by a person’s own immune system. A new small study found that monocytes—a type of white blood cell—expressing a gene called interleukin 1 beta (IL1B) are associated with smaller HIV reservoirs after a person acquires HIV. Further understanding of the influence of IL1B on HIV reservoir size could guide future novel HIV remission strategies.

Clinical trials and animal studies of HIV remission approaches reported outcomes of interventions designed to maintain HIV viral suppression or remission after ART was paused. When ART is paused in an HIV remission study it is called an analytical treatment interruption (ATI). In one study, researchers infected 16 infant monkeys with the simian version of HIV (SHIV), then placed them into three different treatment groups, each including ART with various combinations of the investigational HIV drug leronlimab and the HIV bNAbs called PGT121-LS and VRC07-523-LS. After 27 weeks of treatment, the research team conducted an ATI and observed outcomes by treatment group. Animals that received ART and both HIV bNAbs experienced rapid rebound of detectable SHIV. Two of 6 animals that received ART and leronlimab remained free of detectable virus through 20 weeks after ATI. All of the animals that received ART, leronlimab and the two HIV bNAbs remained free of detectable virus at the time of abstract submission, 15 weeks after ATI. Monitoring and assessment of monkeys’ SHIV reservoirs is ongoing, and further studies are warranted to understand the effects observed, according to the authors.

Novel PrEP Implant Technology 

Available PrEP methods currently include oral pill, long-acting injectable, and controlled release vaginal ring formulations. A novel refillable controlled-release antiretroviral drug (ARV) implant was found to be safe and capable of delivering one or more ARVs. The implant, placed subdermally—just under the skin—was examined in monkeys and demonstrated that it could provide sustained release of the investigational ARVs islatravir and MK-8527 as well as the lenacapavir, which is licensed for ART and being studied for PrEP, and bictegravir and dolutegravir, both licensed for ART. Implants containing islatravir were evaluated for efficacy as PrEP and found to completely protect the animals from SHIV challenge—direct administration of the virus vaginally and rectally—through 29 months. The implant is being studied for delivery of ARVs for PrEP and ART.

HIV clinical research builds upon basic science discoveries, preclinical studies, and consultations with communities affected by HIV. Further, clinical research relies on the dedication of study participants and the people who support them. NIAID is grateful to all who contribute to advancing HIV research.

References

P Ehrenberg et al. Single-cell analyses reveal that monocyte gene expression impacts HIV-1 reservoir size in acutely treated cohorts. HIV Research for Prevention Conference. Tuesday, October 8, 2024.

W Hahn et al. Vaccination with a novel fractional escalating dose strategy improves early humoral responses with a novel germline targeting HIV vaccine (426.mod.core-C4b): preliminary results from HVTN 301. HIV Research for Prevention Conference. Wednesday, October 9, 2024. 

N. Haigwood et al. Short-term combination immunotherapy with broadly neutralizing antibodies and CCR5 blockade mediates ART-free viral control in infant rhesus macaques. HIV Research for Prevention Conference. Wednesday, October 9, 2024.

M Marzinke et al. Evaluation of potential pharmacologic interactions between CAB-LA or TDF/FTC and hormonal contraceptive agents: a tertiary analysis of HPTN 084. HIV Research for Prevention Conference. Thursday, October 10, 2024.

A Mayo et al. Pregnancy and infant outcomes among individuals exposed to dapivirine ring during the first trimester of pregnancy in the MTN-025/HOPE open-label extension trial. HIV Research for Prevention Conference. Thursday, October 10, 2024.

F Pons-Faudoa et al. Drug-agnostic transcutaneously-refillable subdermal implant for ultra-long-acting delivery of antiretrovirals for HIV prevention. HIV Research for Prevention Conference. Wednesday, October 9, 2024.

Discovery, Development and Delivery for an Increasingly Interconnected HIV Landscape 

By Carl Dieffenbach, Ph.D., director, Division of AIDS, NIAID

This blog is the third 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 NIAID HIV clinical research enterprise has celebrated important scientific advances since awards were made to the current networks in 2020. These achievements include the culminating steps in decades of research that led to approval of the first generation of long-acting medications for HIV prevention—a milestone that raises the standard for any future antiretroviral drug development to levels unimaginable even a decade ago. Our research has highlighted opportunities to maintain the overall health of people with HIV throughout their lifespans. We continue to expand the boundaries of scientific innovation in pursuit of durable technologies that could hasten an end to the HIV pandemic, especially preventive vaccines and curative therapy. During the COVID-19 public health emergency, our networks stepped forward to deliver swift results that advanced vaccines and therapeutics within a year of the World Health Organization declaring the global pandemic, while maintaining progress on our HIV research agenda. The impact of this collective scientific progress is evident worldwide.

Together with my NIH colleagues, I express sincere gratitude to the leaders and staff of current clinical trials networks, our research and civil society partners, and most importantly, clinical study participants and their loved ones, for their enduring commitment to supporting science that changes lives.

As we do every seven years, we are at a point in the funding cycle when our Institute 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 and priorities. Subsequent NIAID HIV research investments will build on the conclusions of these discussions.

Looking to the future, we envision an HIV research enterprise that follows a logical evolution in addressing new scientific priorities informed by previous research progress. We will fund our next networks to align with updated research goals to take us through the end of 2034. The HIV research community’s outstanding infrastructure is the model for biomedical research. Now, our capacity must reflect an increasing interdependence across clinical practice areas and public health contexts. Our goals for the next networks are to:

• Maintain our support for core discovery and translational research to address gaps in biomedical HIV prevention and treatment, including a vaccine and therapeutic remission or cure. Our objective is to identify effective interventions that expand user choice and access, as well as improve quality of life across the lifespan;
• Provide the multidisciplinary leadership required to address the intersections between HIV and other diseases and conditions throughout the lifespan, including noncommunicable diseases, such as diabetes mellitus and substance use disorder, and infectious diseases that share health determinants with HIV, such tuberculosis and hepatitis;
• Compress protocol development and approval timelines for small and early-stage trials to enable more timely translation of research concepts to active studies; 
• Respond to discrete implementation science research questions as defined by our implementation counterparts, including federal partners at the Centers for Disease Control and Prevention, Health Resources and Services Administration, U.S. Agency for International Development, agencies implementing the U.S. President’s Emergency Plan for AIDS Relief, and other nongovernmental funders and implementing organizations worldwide;  
• Draw from nimble and effective partnerships at all levels to leverage the necessary combination of financial resources, scientific expertise, and community leadership and operational capacity to perform clinical research that is accessible to and representative of the populations most affected by HIV, especially people and communities that have been underserved in the HIV response; 
• Leverage our partners’ platforms if called on to close critical evidence gaps for pandemic response; and,
• Plan for impact by mapping clear pathways to rapid regulatory decisions, scalable production, and fair pricing before the start of any efficacy study.

Our shared goal is to produce tools and evidence to facilitate meaningful reductions in HIV incidence, morbidity and mortality globally. I invite you to continue sharing your thoughts with us to help shape the future of HIV clinical research, and to review the blogs on specialized topics that we will continue to post on the HIV Clinical Research Enterprise page in the coming weeks. Please share your feedback, comments, and questions at NextNIAIDHIVNetworks@mail.nih.gov. Submissions will be accepted through December 2024.