Selected Grantee Publications
- Clear All
- 12 results found
- Nonhuman Primate Models
- nhlbi
- Vaccines/Therapeutics
Small-Diameter Artery Grafts Engineered from Pluripotent Stem Cells Maintain 100% Patency in an Allogeneic Rhesus Macaque Model
Zhang et al., Cell Reports Medicine. 2025.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00075-8
Globally, the leading cause of death is occlusive arterial disease, but surgical revascularization improves patient prognosis and reduces mortality. Vascular grafts often are needed in coronary bypass surgery for surgical revascularization. However, the clinically approved option for small-diameter revascularization is autologous vascular grafts, which require invasive harvesting methods, and many patients lack suitable vessels. Researchers developed a novel method for graft development using arterial endothelial cells (AECs), derived from pluripotent stem cells (PSCs), on expanded polytetrafluoroethylene using specific adhesion molecules. This study used a 6- to 13-year-old male rhesus macaque arterial interposition grafting model. The major histocompatibility complex mismatched wild-type (MHC-WT) AEC grafts were successful when implanted in rhesus macaques and attracted host cells to the engraftment, leading to 100% patency for 6 months. The results highlight a novel strategy for generating artery grafts from PSC-derived MHC-WT AECs that overcomes current challenges in graft development and may have future clinical applications. Supported by ORIP (P51OD011106, S10OD023526), NCI, and NHLBI.
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.
Stable HIV Decoy Receptor Expression After In Vivo HSC Transduction in Mice and NHPs: Safety and Efficacy in Protection From SHIV
Li, Molecular Therapy. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124088/
Autologous hematopoietic stem cell (HSC) gene therapy offers a promising HIV treatment strategy, but cost, complexity, and toxicity remain significant challenges. Using female mice and female nonhuman primates (NHPs) (i.e., rhesus macaques), researchers developed an approach based on the stable expression of eCD4-Ig, a secreted decoy protein for HIV and simian–human immunodeficiency virus (SHIV) receptors. Their goals were to (1) assess the kinetics and serum level of eCD4-Ig, (2) evaluate the safety of HSC transduction with helper-dependent adenovirus–eCD4-Ig, and (3) test whether eCD4-Ig expression has a protective effect against viral challenge. They found that stable expression of the decoy receptor was achieved at therapeutically relevant levels. These data will guide future in vivo studies. Supported by ORIP (P51OD010425) and NHLBI.
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
AZD5582 Plus SIV-Specific Antibodies Reduce Lymph Node Viral Reservoirs in Antiretroviral Therapy–Suppressed Macaques
Dashti et al., Nature Medicine. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579098/
Researchers are interested in targeting the HIV reservoir via a latency reversal and clearance approach. Previously, investigators demonstrated that AZD5582 induces systemic latency reversal in rhesus macaques and humanized mice, but a consistent reduction in the viral reservoir was not observed. In the current study, they combined AZD5582 with four simian immunodeficiency virus (SIV)–specific rhesus monoclonal antibodies using rhesus macaques of both sexes. They reported a reduction in total and replication-competent SIV DNA in lymph node–derived CD4+ T cells in the treated macaques. These findings provide proof of concept for the potential of the latency reversal and clearance HIV cure strategy. Supported by ORIP (P51OD011132, R01OD011095), NIAID, NCI, and NHLBI.
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+ Lymphocytes Do Not Impact SIV Reservoir Establishment under ART
Statzu et al., Nature Microbiology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894752/
The HIV-1 latent reservoir has been shown to persist following antiretroviral therapy (ART), but the mechanisms underlying the establishment and maintenance of the reservoir are not fully understood. Using rhesus macaques of both sexes, investigators examined the effects of CD8+ T cells on formation of the latent reservoir with simian immunodeficiency virus (SIV) infection. They found that CD8+ T cell depletion resulted in slower decline of viremia but did not change the frequency of infected CD4+ T cells in the blood or lymph nodes. Additionally, the size of the persistent reservoir was unchanged. These findings suggest that the viral reservoir is established largely independent of SIV-specific cytotoxic T lymphocyte control. Supported by ORIP (P51OD011132), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
Generation of SIV-Resistant T Cells and Macrophages from Nonhuman Primate Induced Pluripotent Stem Cells with Edited CCR5 Locus
D’Souza et al., Stem Cell Reports. 2022.
https://www.doi.org/10.1016/j.stemcr.2022.03.003
Genetically modified T cells have shown promise as a potential therapy for HIV. A renewable source of T cells from induced pluripotent stem cells (iPSCs) could help to further research progress in this area. The researchers used Mauritian cynomolgus macaques to generate simian immunodeficiency virus (SIV)–resistant T cells and macrophages from iPSCs. These engineered cells demonstrated impaired capacity for differentiation into CD4+CD8+ T cells. T cells and macrophages from the edited iPSCs did not support SIV replication. These findings could be applied to the development of new HIV therapies. Supported by ORIP (R24OD021322, P51OD011106) and NHLBI.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
Inflammatory Blockade Prevents Injury to the Developing Pulmonary Gas Exchange Surface in Preterm Primates
Toth et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abl8574
Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25% to 40% of preterm births. Investigators used a prenatal rhesus macaque model to assess how fetal inflammation could affect lung development. They found that inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure. Blockade of the inflammatory cytokines IL-1β and TNFα ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells. These data provide new insight into key mechanisms of developmental lung injury and highlight targeted inflammatory blockade as a potential therapeutic approach to ameliorate lung injury in the neonatal population. Supported by ORIP (P51OD011107), NIAID, NHLBI, NICHD, and NIEHS.