Selected Grantee Publications
- Clear All
- 237 results found
- Nonhuman Primate Models
- New Approach Methodologies
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
Rhesus Macaques Build New Social Connections After a Natural Disaster
Testard et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221003687
Climate change has increased the frequency and intensity of weather-related disasters such as hurricanes and floods. In 2017, Puerto Rico suffered its worst natural disaster, Hurricane Maria, leaving 3,000 dead and provoking a mental health crisis. Cayo Santiago Island, home to a population of rhesus macaques (Macaca mulatta), was devastated by this storm. Testard et al. compared social networks of two groups of macaques before and after the hurricane and found an increase in affiliative social connections, driven largely by monkeys most socially isolated before Hurricane Maria. Further analysis revealed monkeys invested in building new relationships rather than strengthening existing ones. Supported by ORIP (P40OD012217), NIA, and NIMH.
Sensitive Tracking of Circulating Viral RNA Through All Stages of SARS-CoV-2 Infection
Huang et al., Journal of Clinical Investigation. 2021.
https://www.jci.org/articles/view/146031
Circulating SARS-CoV-2 RNA could represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples. Researchers developed a CRISPR-amplified, blood-based COVID-19 (CRISPR-ABC) assay to detect SARS-CoV-2 in plasma. They evaluated the assay using samples from SARS-CoV-2-infected African green monkeys and rhesus macaques, as well as from COVID-19 patients. CRISPR-ABC consistently detected viral RNA in the plasma of the experimentally infected primates from 1 to 28 days after infection. The increases in plasma SARS-CoV-2 RNA in the monkeys preceded rectal swab viral RNA increases. In the patient cohort, the new assay demonstrated 91.2% sensitivity and 99.2% specificity versus RT-qPCR nasopharyngeal testing, and it also detected COVID-19 cases with transient or negative nasal swab RT-qPCR results. These findings suggest that detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR could improve COVID-19 diagnosis, facilitate the evaluation of SARS-CoV-2 infection clearance, and help predict the severity of infection. Supported by ORIP (P51OD011104).
Cytomegaloviral Determinants of CD8+ T Cell Programming and RhCMV/SIV Vaccine Efficacy
Malouli et al., Science Immunology. 2021.
https://www.science.org/doi/10.1126/sciimmunol.abg5413
Cytomegalovirus (CMV)-based vaccine vectors were developed to leverage the ability of CMVs to elicit sustained CD4+ and CD8+ T cell responses with broad tissue distribution. The 68-1 rhesus cytomegalovirus (RhCMV) vectors that express simian immunodeficiency virus (SIV) inserts induce major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8+T cell responses. The contribution of this unconventional MHC restriction to RhCMV/SIV vaccine efficacy are poorly understood. Researchers demonstrated that these responses result from genetic rearrangements in 68-1 RhCMV that disrupt the function of eight immunomodulatory proteins encoded by the virus. Repair of each of these genes with either RhCMV or human CMV counterparts shifted responses to MHC-Ia-restricted, or MHC-Ia- and MHC-II-restricted, CD8 T cell responses, but repairing the RhCMV genes did not protect against SIV. These findings suggest that MHC-E-restricted CD8+ T cell responses may be critical to protection against SIV. Supported by ORIP (U42OD023038, P51OD011092).
Metabolomics Analysis of Follicular Fluid Coupled With Oocyte Aspiration Reveals Importance of Glucocorticoids in Primate Periovulatory Follicle Competency
Ravisankar et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-85704-6
Assisted reproductive therapy in primates requires ovarian stimulation protocols, which result in multiple heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. Recovered oocytes from rhesus macaque follicles (n=74 follicles) were fertilized in vitro and classified as failed to cleave, cleaved but arrested, or able to form blastocysts. Metabolomics analysis of the follicular fluid identified 60 metabolites that were different among embryo classifications; key was an increase in the intrafollicular ratio of cortisol to cortisone in the blastocyst group, which was associated with translocation of the glucocorticoid receptor, NR3C1. The data suggest a role for NR3C1 in the regulation of follicular processes, such as expansion of cumulus granulosa cells, via paracrine signaling. Supported by ORIP (P51OD011092) and NICHD.
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.
Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies Against the SHIV Challenge Virus but Not with V1V2 Vaccine–Induced Anti-V2 Antibodies Alone
Hessell et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001010
In the RV144 human immunodeficiency virus (HIV) vaccine trial, the only immune response associated with reduced infection was a high level of antibodies (Abs) targeting the second variable (V2) loop of the HIV envelope protein (Env). The mechanism underlying this suggested contribution of V2 Abs to protection remains unknown. Researchers tested the role of vaccine-induced anti-V2 Abs in rhesus macaques. Three vaccines strategies were designed to induce only V1V2 Abs before simian-human immunodeficiency virus (SHIV) challenge. Vaccine-induced V2 Abs did not independently control SHIV infection. However, neutralizing and virus capture anti-Env Abs were found to correlate with SHIV control. Supported by ORIP (P51OD011092) and NIAID.
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.
New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure
Li et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00071-21
Researchers knew that substitution of HIV-1 Env residue 375-serine by aromatic residues enhances binding to rhesus CD4 enabling primary HIV-1 Envs to support replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus monkeys. The investigators constructed SHIVs containing 10 primary Envs corresponding to HIV-1 subtypes A, B, C, AE, and AG. Only one with histidine at Env375 replicated efficiently in rhesus cells. Replacement of wild-type Env375 residues by tryptophan, tyrosine, phenylalanine, or histidine in the other 9 SHIVs led to efficient replication. These new SHIVs transmit via mucosal routes like HIV-1 and have use for vaccine testing in nonhuman primates. Supported by ORIP (U42OD021458, P40OD012217), NIAID, and NCI.
Autologous Transplant Therapy Alleviates Motor and Depressive Behaviors in Parkinsonian Monkeys
Tao et al., Nature Medicine. 2021.
https://www.nature.com/articles/s41591-021-01257-1
Generation of induced pluripotent stem cells (iPSCs) enables standardized of dopamine (DA) neurons for autologous transplantation therapy to improve motor functions in Parkinson disease (PD). Adult male rhesus PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs of PD over a 2-year period without immunosuppressive therapy. Mathematical modeling showed correlations between surviving DA neurons with PET signal intensity and behavior recovery regardless of autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number. The results demonstrate favorable efficacy of the autologous transplant approach to treat PD. Supported by ORIP (P51OD011106) NINDS, and NICHD.