Selected Grantee Publications
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- 27 results found
- Nonhuman Primate Models
- Pediatrics
- Rare Diseases
Immune Perturbation Following SHIV Infection Is Greater in Newborn Macaques Than in Infants
Shapiro et al., JCI Insight. 2024.
https://pubmed.ncbi.nlm.nih.gov/39190496
This study investigates immune perturbation following simian-human immunodeficiency virus (SHIV) infection in newborn and infant male and female rhesus macaques, highlighting significant differences in pathogenesis. Although plasma viremia and lymph node viral DNA were similar, newborns exhibited higher viral DNA levels in gut and lymphoid tissues 6–10 weeks postinfection than infants. Additionally, newborns showed greater immune alterations, with skewed monocyte and CD8+ T-cell profiles and minimal type I interferon responses. These findings suggest age-dependent immunological responses to SHIV and underscore the vulnerability of newborns to HIV-related pathogenesis, providing insights into immune development and pediatric HIV management. Supported by ORIP (P51OD011092, U42OD023038, U42OD010426) and NIAID.
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
Human Stem Cell-Derived Cardiomyocytes Integrate Into the Heart of Monkeys With Right Ventricular Pressure Overload
Scholz et al., Cell Transplantation. 2024.
https://journals.sagepub.com/doi/10.1177/09636897241290367
Patients with single-ventricle congenital heart defects suffer from right ventricular pressure overload (RVPO). Researchers developed a novel pulmonary artery banding (PAB) rhesus macaque model to induce RVPO. This study investigated the efficacy of human induced pluripotent stem cell cardiac lineage cell (hiPSC-CL) delivery at low or high dose into adult male and female rhesus macaques with right ventricular dysfunction. The findings indicate that hiPSC-CLs were successfully grafted and integrated to match the surrounding host right ventricle myocardium. These results suggest hiPSC-CL therapy is a potential adjunctive treatment for RVPO, but future research will be needed to elucidate the beneficial effects. Supported by ORIP (P51OD011106).
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.
Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Nelson et al., Science Immunology. 2024.
https://www.science.org/doi/10.1126/sciimmunol.adm7097
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env—SOSIP—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut. Supported by ORIP (P51OD011107), NCI, and NIAID.
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.
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.
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.
Conjugation of HIV-1 Envelope to Hepatitis B Surface Antigen Alters Vaccine Responses in Rhesus Macaques
Nettere et al., NPJ Vaccines. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673864/
Researchers are interested in developing an HIV-1 vaccine that improves upon the regimen used in the RV144 clinical trial. The authors tested the hypothesis that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T-cell help and improve antibody production against HIV-1. Using juvenile rhesus macaques of both sexes, they evaluated the immunogenicity of their conjugate regimen. Their findings suggest that conjugate vaccination can engage both HIV-1 Env– and hepatitis B surface antigen–specific Tcell help and modify antibody responses at early time points. This work may help inform future efforts to improve the durability and efficacy of next-generation HIV vaccines. Supported by ORIP (P51OD011107, K01OD024877) and NIAID.