Selected Grantee Publications
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
Interferon Regulatory Factor 7 Modulates Virus Clearance and Immune Responses to Alphavirus Encephalomyelitis
Troisi et al., Journal of Virology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37772825/
Interferon regulatory factor 7 (IRF7)–deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7-/- mice produce low levels of IFN-α but high levels of IFN-β with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7-/- mice developed inflammation earlier but failed to clear virus from motor neuron–rich regions of the brainstem and spinal cord. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance. Supported by ORIP (T32OD011089, R01OD01026529) NINDS, and NIAID.
Antiretroviral Therapy Ameliorates Simian Immunodeficiency Virus–Associated Myocardial Inflammation by Dampening Interferon Signaling and Pathogen Response in the Heart
Robinson et al., The Journal of Infectious Diseases. 2023.
https://doi.org/10.1093/infdis/jiad105
HIV is associated with increased risk of cardiovascular disease, but the underlying mechanisms are not fully understood. Using RNA sequencing, investigators characterized the effects of simian immunodeficiency virus (SIV) infection on the hearts of male rhesus macaques. They demonstrated that SIV infection drives a canonical antiviral response in the heart, as well as dysregulation of genes involved in fatty acid shuttling and metabolism. Their findings suggest that antiretroviral therapy helps mitigate immune activation during viremic conditions and plays a cardioprotective role. Future studies are needed to assess the long-term effects of these dynamics. Supported by ORIP (P51OD011104), NIAID, NIMH, and NINDS.
Focused Ultrasound–Mediated Brain Genome Editing
Lao et al., PNAS. 2023.
https://www.pnas.org/doi/epdf/10.1073/pnas.2302910120
Gene editing in the brain has been challenging because of the restricted transport imposed by the blood–brain barrier (BBB). In this study, investigators described a safe and effective gene‑editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR machinery to the brain in mice. By combining FUS with adeno-associated virus–mediated gene delivery, researchers can achieve more than 25% editing efficiency of particular cell types. This method has the potential to expand toolkit options for CRISPR delivery and opens opportunities for treating diseases of the brain, such as neurodegenerative disorders, with somatic genome editing. Supported by ORIP (U42OD026635) and NINDS.
Diverse Targets of SMN2-Directed Splicing-Modulating Small Molecule Therapeutics for Spinal Muscular Atrophy
Ottesen et al., Nucleic Acids Research. 2023.
https://academic.oup.com/nar/article/51/12/5948/7110763?login=true
Spinal muscular atrophy (SMA) results from deletions or mutations of the SMN1 gene. SMN2 is a nearly identical copy of SMN1 but cannot compensate for its loss. Manipulation of splicing to restore SMN2 exon 7 inclusion provides a promising therapeutic avenue for SMA, and two small-molecule agents—risdiplam and branaplam—restore body-wide inclusion of the SMN2 exon 7 upon oral administration. In this study, researchers demonstrate the advantages of combined treatments with low doses of risdiplam and branaplam. These findings can be applied to develop the next generation of small‑molecule therapeutics, with a focus on better efficacies and fewer off-target effects. Supported by ORIP (T35OD027967) and NINDS.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Longitudinal Characterization of Circulating Extracellular Vesicles and Small RNA During Simian Immunodeficiency Virus Infection and Antiretroviral Therapy
Huang et al., AIDS. 2023.
https://www.doi.org/10.1097/QAD.0000000000003487
Antiretroviral therapy is effective for controlling HIV infection but does not fully prevent early aging disorders or serious non-AIDS events among people with HIV. Using pigtail and rhesus macaques (sex not specified), researchers profiled extracellular vesicle small RNAs during different phases of simian immunodeficiency virus infection to explore the potential relationship between extracellular vesicle–associated small RNAs and the infection process. They reported that average particle counts correlated with infection, but the trend could not be explained fully by virions. These findings raise new questions about the distribution of extracellular vesicle RNAs in HIV latent infection. Supported by ORIP (U42OD013117), NIDA, NIMH, NIAID, NCI, and NINDS.
Mechanism of STMN2 Cryptic Splice-Polyadenylation and its Correction for TDP-43 Proteinopathies
Baughn et al., Science. 2023.
Loss of the RNA-binding protein TDP-43 from the nuclei of affected neurons is a hallmark of neurodegeneration in TDP-43 proteinopathies (e.g., amyotrophic lateral sclerosis, frontotemporal dementia). Loss of functional TDP-43 is accompanied by misprocessing of the stathmin-2 (STMN2) RNA precursor. Investigators determined the elements through which TDP‑43 regulates STMN2 pre‑mRNA processing and identified steric binding antisense oligonucleotides that are capable of restoring normal STMN2 protein and RNA levels. This approach is potentially applicable for human therapy. Supported by ORIP (U42OD010921), NIA, NCI, NIGMS, and NINDS.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.