Selected Grantee Publications
Lipid Droplets and Peroxisomes Are Co-Regulated to Drive Lifespan Extension in Response to Mono-Unsaturated Fatty Acids
Papsdorf et al., Nature Cell Biology. 2023.
https://www.nature.com/articles/s41556-023-01136-6
Investigators studied the mechanism by which mono-unsaturated fatty acids (MUFAs) extend longevity. They found that MUFAs upregulated the number of lipid droplets in fat storage tissues of Caenorhabditis elegans, and increased lipid droplets are necessary for MUFA-induced longevity and predicted remaining lifespan. Lipidomics data revealed that MUFAs modify the ratio of membrane lipids and ether lipids, which leads to decreased lipid oxidation in middle-aged individuals. MUFAs also upregulate peroxisome number. A targeted screen revealed that induction of both lipid droplets and peroxisomes is optimal for longevity. This study opens new interventive avenues to delay aging. Supported by ORIP (S10OD025004, S10OD028536, P40OD010440), NIA, NCCIH, NIDDK, and NHGRI.
Investigation of Monoclonal Antibody CSX-1004 for Fentanyl Overdose
Bremer et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/38052779/
The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl and has led to more than 70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, the authors present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice, CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Using a highly translational nonhuman primate model for respiratory depression, they demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3–4 weeks. These data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose. Supported by ORIP (P40OD010938) and NIDA.
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.
Timing of Initiation of Anti-Retroviral Therapy Predicts Post-Treatment Control of SIV Replication
Pinkevych et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558076/
Researchers are interested in approaches to reducing viral rebound following interruption of antiretroviral therapy, but more work is needed to understand major factors that determine the viral “setpoint” level. Researchers previously assessed how timing of treatment can affect the frequency of rebound from latency. In the current study, the authors analyzed data from multiple studies of simian immunodeficiency virus (SIV) infection in rhesus macaques to further explore the dynamics and predictors of post-treatment viral control. They determined that the timing of treatment initiation was a major predictor of both the level and the duration of post-rebound SIV control. These findings could help inform future treatments. Supported by ORIP (U42OD011023, P51OD011132, P51OD011092), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS
Whole Genome Analysis for 163 gRNAs in Cas9-Edited Mice Reveals Minimal Off-Target Activity
Peterson et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04974-0
CRISPR/Cas9 genome editing offers potential as a treatment for genetic diseases in humans. Using whole-genome sequencing, investigators assessed the occurrence of Streptococcus pyogenes Cas9–induced off-target mutagenesis in Cas9-edited founder mice. Sequencing and computational analysis indicate that the risk of Cas9 cutting at predicted off-target sites is lower than random genetic variation introduced into the genomes of inbred mice through mating. These findings will inform future design and use of Cas9-edited animal models and can provide context for evaluating off-target potential in genetically diverse patient populations. Supported by ORIP (UM1OD023221, UM1OD023222) and NHGRI.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.
Cannabinoid Enhancement of lncRNA MMP25-AS1/MMP25 Interaction Reduces Neutrophil Infiltration and Intestinal Epithelial Injury in HIV/SIV Infection
Premadasa et al., Journal of Clinical Investigation Insight. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132162/
Gastrointestinal CD4+ T cell depletion during acute simian immunodeficiency virus (SIV) and HIV infection causes significant structural and functional damage, disrupting intestinal immune homeostasis and leading to intestinal epithelial barrier dysfunction. Oral phytocannabinoids are safe and well tolerated in people with HIV, but more information is needed regarding the effects of long-term tetrahydrocannabinol (THC) use on the intestinal epithelial compartment. Investigators profiled gene expression in the colonic epithelium of SIV-infected rhesus macaques of both sexes that were administered THC. They reported that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury, potentially by downregulating MMP25 expression through modulation of a long noncoding RNA, MMP25-AS1. Supported by ORIP (P51OD011104, P51OD011103), NIAID, and NIDA.
Resolution of Structural Variation in Diverse Mouse Genomes Reveals Chromatin Remodeling due to Transposable Elements
Ferraj et al., Cell Genomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203049/
Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. Here, investigators used long-read whole genome sequencing to assemble the genomes of 20 diverse inbred laboratory strains of mice. From whole-genome comparisons, they generated a sequence-resolved callset of 413,758 structural variants. These data are presented as a comprehensive resource that can be used for future genomic studies, aid in modeling and studying the effects of genetic variation, and enhance genotype-to-phenotype research. Supported by ORIP (R24OD021325), NCI, NIGMS, and NHGRI.
Topologically Associating Domain Boundaries Are Required for Normal Genome Function
Rajderkar et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04819-w
Eukaryotic genomes fold into topologically associating domains (TADs), sub-megabase-scale chromatin segments characterized by high intra-domain chromatin contact frequency. Investigators selected eight independent TAD boundaries in the vicinity of genes active during embryonic development, individually deleted these boundaries from the mouse genome, and systematically examined the consequences on survival, genome organization, gene expression, and development. Results of the studies demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to consider the potential pathogenicity of deletions affecting TAD boundaries in clinical genetics screening. Supported by ORIP (UM1OD023221), NIGMS, and NHGRI.