Selected Grantee Publications
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.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Zilberg et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-023-44601-4
The authors reported the cryogenic electron microscopy structure of human trace amine-associated receptor 1 (hTAAR1, hTA1) signaling complex, a key modulator in monoaminergic neurotransmission, as well as its similarities and differences with other TAAR members and rodent TA1 receptors. This discovery has elucidated hTA1’s molecular mechanisms underlining the strongly divergent pharmacological properties of human and rodent TA1 and therefore will boost the translation of preclinical studies to clinical applications in treating disorders of dopaminergic dysfunction, metabolic disorders, cognitive impairment, and sleep-related dysfunction. Supported by ORIP (S10OD019994, S10OD026880, and S10OD030463), NIDA, NIGMS, NIMH, and NCATS.
Lymphoid Tissues Contribute to Plasma Viral Clonotypes Early After Antiretroviral Therapy Interruption in SIV-Infected Rhesus Macaques
Solis-Leal et al., Science Translational Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/38091409/
Researchers are interested in better understanding the sources, timing, and mechanisms of HIV rebound that occurs after interruption of antiretroviral therapy (ART). Using rhesus macaques (sex not specified), investigators tracked barcoded simian immunodeficiency virus (SIV) clonotypes over time and among tissues. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. Additionally, the authors reported that CD4+ T cells harbored the most viral RNA after ART interruption. These tissues are likely to contribute to viral reactivation and rebound after ART interruption, but further studies are needed to evaluate the relative potential contributions from other tissues and organs. Supported by ORIP (P51OD011104, P51OD011133, S10OD028732, S10OD028653), NCI, NIMH, and NINDS.