Selected Grantee Publications
- 486 results found
Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41
Schiffner et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38816615
Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.
Natural Killer–Like B Cells Are a Distinct but Infrequent Innate Immune Cell Subset Modulated by SIV Infection of Rhesus Macaques
Manickam et al., PLOS Pathogens. 2024.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012223
Natural killer–like B (NKB) cells express both natural killer (NK) and B cell receptors. Intracellular signaling proteins and trafficking markers were expressed differentially on naive NKB cells. CD20+ NKG2A/C+ NKB cells were identified in organs and lymph nodes of naive rhesus macaques (RMs). Single-cell RNA sequencing (scRNAseq) of sorted NKB cells confirmed that NKB cells are unique, and transcriptomic analysis of naive splenic NKB cells by scRNAseq showed that NKB cells undergo somatic hypermutation and express Ig receptors, similar to B cells. Expanded NKB frequencies were observed in RM gut and buccal mucosa after simian immunodeficiency virus (SIV) infection, and mucosal and peripheral NKB cells were associated with colorectal cytokine milieu and oral microbiome changes. NKB cells gated on CD3-CD14-CD20+NKG2A/C+ cells were inclusive of transcriptomically conventional B and NK cells in addition to true NKB cells, confounding accurate phenotyping and frequency recordings. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
Physiologically Based Pharmacokinetic Model Validated to Enable Predictions of Multiple Drugs in a Long-Acting Drug-Combination Nano-Particles (DcNP): Confirmation With 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products
Perazzolo et al., Journal of Pharmaceutical Sciences. 2024.
https://jpharmsci.org/article/S0022-3549(24)00060-1/fulltext
Drug-combination nanoparticles synchronize delivery of multiple drugs in a single, long-acting, targeted dose. Two distinct classes of long-acting injectable products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site, and Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access. This review used data from three nonhuman primate studies, consisting of nine pharmacokinetic data sets, to support clinical development of Class II products. Eight of nine models passed validation, and the drug–drug interaction identified in the ninth model can be accounted for in the final model. Supported by ORIP (P51OD010425, U42OD011123), NIAID, and NHLBI.
Persistence of a Skewed Repertoire of NK Cells in People With HIV-1 on Long-Term Antiretroviral Therapy
Anderko et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38551350
HIV-1 infection alters the natural killer (NK) cell phenotypic and functional repertoire. A rare population of FcRγ−NK cells exhibiting characteristics of traditional immunologic memory expands in people with HIV. In a longitudinal analysis during the first 4 years of antiretroviral therapy (ART), a skewed repertoire of cytokine unresponsive FcRγ−memory-like NK cells persisted in people with HIV, and surface expression of CD57 and KLRG1 increased, suggesting progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing antibody titers to human cytomegalovirus (CMV), with human CMV viremia detected in approximately one-third of people studied during the first 4 years of ART. About 40% of people studied displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis. These findings indicate that NK cell irregularities persist in people with HIV despite long-term ART. Supported by ORIP (P51OD011132, S10OD026799), NIAID, and NHLBI.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Nam, Cancer Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38588407/
Tumor-initiating cells can survive in harsh environments via stress tolerance and metabolic flexibility; studies on this topic can yield new targets for cancer therapy. Using cultured cells and live human surgical biopsies of non-small cell lung cancer, researchers demonstrated that nutrient stress drives a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. This cascade results from upregulation of integrin αvβ3, a cancer stem cell marker. In mice, pharmacological or genetic targeting prevented lung cancer cells from evading the effects of nutrient stress, thus blocking tumor initiation. This work suggests that this molecular pathway leads to cancer stem cell reprogramming and could be linked to metabolic flexibility and tumor initiation. Supported by ORIP (K01OD030513), NCI, NIGMS, and NINDS.
Transcriptome- and Proteome-Wide Effects of a Circular RNA Encompassing Four Early Exons of the Spinal Muscular Atrophy Genes
Luo, Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/38714739/
Spinal muscular atrophy (SMA) is a leading genetic cause of mortality in infants and often results from a deficiency of deletions of or mutations in the SMN1 gene. In this study, researchers report the transcriptome- and proteome-wide effects of overexpression of C2A‑2B3-4, a circular RNA produced by SMN1 and SMN2, in cells. They report that C2A-2B-3-4 is associated with expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation, and neuromuscular junction formation. More work is needed to investigate the role of these genes in processes associated with SMA and other pathological conditions, including cancer and male infertility. Supported by ORIP (T35OD027967) and NINDS.
CD8+ T Cell Targeting of Tumor Antigens Presented by HLA-E
Iyer, Science Advances. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086602/
Researchers have hypothesized that human leukocyte antigen-E (HLA-E)–positive cancer cells could be targeted by HLA-E–restricted CD8+ T cells. In this study, the authors assessed whether major histocompatibility complex E (MHC-E) expression by cancer cells can be targeted for MHC-E–restricted T cell control. Using male rhesus macaques, they found that a cytomegalovirus can be used as a vector to generate specific immune cells that can target cancer cells. The authors conclude that targeting HLA-E with restricted, specific CD8+ T cells could offer a new approach for immunotherapy of prostate cancer. Overall, this study supports the concept of a cancer vaccine. Supported by ORIP (P51OD011092) and NIAID.
A Revamped Rat Reference Genome Improves the Discovery of Genetic Diversity in Laboratory Rats
de Jong, Cell Genomics. 2024.
https://www.cell.com/cell-genomics/fulltext/S2666-979X(24)00069-7
Rattus norvegicus has been used in many fields of study related to human disease; its genome was sequenced shortly after the genomes of Homo sapiens and Mus musculus. Investigators report extensive analyses of the improvements in mRatBN7.2, compared with the previous version. They conducted a broad analysis of a whole-genome sequencing data set of 163 samples from 120 inbred rat strains and substrains. Several additional resources have been created. This new assembly and its associated resources create a more solid platform for research on the many dimensions of physiology, behavior, and pathobiology of rats and can provide more reliable and meaningful translation of findings to human populations. Supported by ORIP (R24OD024617), NHGRI, NHLBI, and NIDA.
Controlled Stiffness of Direct-Write, Near-Field Electrospun Gelatin Fibers Generates Differences in Tenocyte Morphology and Gene Expression
Davis, Journal of Biomechanical Engineering. 2024.
https://pubmed.ncbi.nlm.nih.gov/38529730/
Tendinopathy is associated with mobility issues, and the cell–matrix interactions involved in the development of tendinopathy are not fully understood. In this study, researchers fabricated micron-scale fibrous scaffolds that mimic native collagen fiber size and orientation. They reported that matrix metalloproteinase and proteoglycans (possible indicators of tendinopathy) were more upregulated in the presence of high-stiffness fibers than low-stiffness fibers. The authors’ findings suggest that scaffolds can serve as in vitro models for tendinopathy. Additionally, their work suggests that matrix mechanical properties contribute to cell–matrix interactions during tendinopathy formation. Supported by ORIP (T32OD011130) and NIA.
Surgical Protocol for Partial Heart Transplantation in Growing Piglets
Medina, World Journal for Pediatric and Congenital Heart Surgery. 2024.
https://pubmed.ncbi.nlm.nih.gov/38780414/
Researchers are interested in using partial heart transplantation (i.e., only the part of the heart containing the necessary heart valve is transplanted) to deliver growing heart valve implants. This novel technique allows partial heart transplants to grow, similar to the valves in heart transplants. More work is needed, however, to understand the underlying biological mechanisms of this approach and achieve progress in clinical care. In the present study, the authors present a surgical protocol for partial heart transplantation in growing piglets. This model will enable other researchers to seek fundamental knowledge about the nature of partial heart transplants. Supported by ORIP (U42OD011140) and NHLBI.