Selected Grantee Publications
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
Spatiotemporal Characterization of Cyclooxygenase Pathway Enzymes During Vertebrate Embryonic Development
Leathers et al., Developmental Biology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39581452/
The cyclooxygenase (COX) pathway plays a fundamental role in embryonic development. Disruptions of the COX pathway during pregnancy cause developmental anomalies, including craniofacial clefts, impaired gut innervation, and neural tube defects in the embryo. Researchers used Gallus gallus embryos to study the expression of COX pathway enzymes during neurulation. COX-1 protein expression was upregulated in cells undergoing mitosis, whereas COX-2 protein expression was ubiquitous. This study provides spatiotemporal expression data of COX pathway enzymes at key embryonic development stages in G. gallus and guides future studies focused on defining the role of these enzymes during embryonic development. Supported by ORIP (T35OD010956), NEI, NIDCR, and NIGMS.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
Immune Restoration by TIGIT Blockade is Insufficient to Control Chronic SIV Infection
Webb et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38775481/
T-cell exhaustion from prolonged upregulation of immune checkpoint receptors (ICR) contributes to immune dysfunction and viral persistence of both human and simian immunodeficiency virus (HIV/SIV) infection. Previous in vitro research has demonstrated the potential use of ICR blockade as a therapeutic. Researchers used a monoclonal antibody targeting humanized T cell immunoreceptor with Ig and ITIM domain (TIGIT) in male and female cynomolgus macaque and female rhesus macaque SIV models, 4–14 years of age. TIGIT blockade was well tolerated, with moderately increased proliferation of T cells and natural killer cells, but a reduction in plasma viral load was not observed. Future research to eliminate SIV should combine ICR blockades with other immunotherapies. Supported by ORIP (P51OD011092), NIAID, and NIMH.
Immune Gene Regulation Is Associated With Age and Environmental Adversity in a Nonhuman Primate
Watowich et al., Molecular Ecology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39032090
The mammalian aging process involves a decline in physiological function, influenced by molecular mechanisms like epigenetic changes. These processes have been studied in controlled settings, however the role of aging in naturalistic populations remains unclear. This study explored the effects of environmental stressors (i.e., Hurricane Maria) on DNA methylation in free-living male and female rhesus macaques in Cayo Santiago, Puerto Rico. Results showed that environmental adversity accelerated age-related molecular changes, especially in gene transcription regions, while primary aging mainly affected nonregulatory regions. These findings highlight how the biology of aging is influenced by environmental factors. Supported by ORIP (P40OD012217), NIA, and NIMH.
SIV-Specific Antibodies Protect Against Inflammasome-Driven Encephalitis in Untreated Macaques
Castell et al., Cell Reports. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11552693
Viral infections are the most common infectious cause of encephalitis, and simian immunodeficiency virus (SIV)–infected macaques are a well-established model for HIV. Researchers investigated the protective effects of SIV-specific antibodies against inflammation-driven encephalitis in using untreated, SIV-infected, male and female pigtail and rhesus macaques. Findings indicate that these antibodies reduce neuroinflammation and encephalitis, highlighting the importance of antibodies in controlling neuroimmune responses, especially in the absence of antiretroviral therapy. This study provides insight into immune-modulatory approaches to combating inflammation-driven encephalopathies. Supported by ORIP (U42OD013117, T32OD011089), NIDA, NHLBI, NIAID, NINDS, and NIMH.
The Effect of Common Paralytic Agents Used for Fluorescence Imaging on Redox Tone and ATP Levels in Caenorhabditis elegans
Morton et al., PLOS One. 2024.
https://pubmed.ncbi.nlm.nih.gov/38669260
Caenorhabditis elegans is a highly valuable model organism in biological research. However, these worms must be paralyzed for most imaging applications, and the effect that common chemical anesthetics may have on the parameters measured—especially biochemical measurements such as cellular energetics and redox tone—is poorly understood. In this study, the authors used two reporters—QUEEN-2m for relative ATP levels and reduction-oxidation–sensitive green fluorescent protein for redox tone—to assess the impact of commonly used chemical paralytics. The results show that all chemical anesthetics at doses required for full paralysis alter redox tone and/or ATP levels, and anesthetic use alters the detected outcome of rotenone exposure on relative ATP levels and redox tone. Therefore, it is important to tailor the use of anesthetics to different endpoints and experimental questions and to develop less disruptive paralytic methods for optimal imaging of dynamic in vivo reporters. Supported by ORIP (P40OD010440, R44OD024963) and NIEHS.
Systematic Multi-trait AAV Capsid Engineering for Efficient Gene Delivery
Eid et al., Nature Communications. 2024.
https://doi.org/10.1038/s41467-024-50555-y
Engineering novel functions into proteins while retaining desired traits is a key challenge for developers of viral vectors, antibodies, and inhibitors of medical and industrial value. In this study, investigators developed Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait adeno-associated virus (AAV) capsids. Fit4Function was used to generate reproducible screening data from a capsid library that samples the entire manufacturable sequence space. The Fit4Function data were used to train accurate sequence-to-function models, which were combined to develop a library of capsid candidates. Compared to AAV9, top candidates from the Fit4Function capsid library exhibited comparable production yields; more efficient murine liver transduction; up to 1,000-fold greater human hepatocyte transduction; and increased enrichment in a screen for liver transduction in macaques. The Fit4Function strategy enables prediction of peptide-modified AAV capsid traits across species and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits. Supported by ORIP (P51OD011107, U42OD027094), NIDDK, NIMH, and NINDS.
RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology
Huang et al., The Journal of Infectious Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/38079216/
Brain tissue–derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in HIV CNS pathology. Using brain homogenate (BH) and bdEVs from male pigtailed macaques, researchers identified dysregulated RNAs in acute and chronic infection. Most dysregulated messenger RNAs (mRNAs) in bdEVs reflected dysregulation in source BH, and these mRNAs are disproportionately involved in inflammation and immune responses. Additionally, several circular RNAs were differentially abundant in source tissue and might be responsible for specific differences in small RNA levels in bdEVs during simian immunodeficiency virus (SIV) infection. This RNA profiling shows potential regulatory networks in SIV infection and SIV-related CNS pathology. Supported by ORIP (U42OD013117), NCI, NIAID, NIDA, NIMH, and NINDS.
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.