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- Nonhuman Primate Models
- Imaging
Molecular Insights Into Antibody-Mediated Protection Against the Prototypic Simian Immunodeficiency Virus
Zhao et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32783-2
Most simian immunodeficiency virus (SIV) vaccines have focused on inducing T cell responses alone or in combination with non-neutralizing antibody responses. To date, studies investigating neutralizing antibody (nAb) responses to protect against SIV have been limited. In this study, researchers isolated 12 potent monoclonal nAbs from chronically infected rhesus macaques of both sexes and mapped their binding specificities on the envelope trimer structure. They further characterized the structures using cryogenic electron microscopy, mass spectrometry, and computational modeling. Their findings indicate that, in the case of humoral immunity, nAb activity is necessary and sufficient for protection against SIV challenge. This work provides structural insights for future vaccine design. Supported by ORIP (P51OD011106), NIAID, and NCI.
Parallel Processing, Hierarchical Transformations, and Sensorimotor Associations along the “Where” Pathway
Doudlah et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.78712
Visually guided behaviors require the brain to transform ambiguous retinal images into object-level spatial representations and map those representations to motor responses. These capabilities are supported by the dorsal “where” pathway in the brain, but the specific contributions of areas along this pathway have remained elusive. Using a rhesus macaque model, researchers compared neuronal activity in two areas along the “where” pathway that bridge the parieto-occipital junction: intermediate visual area V3A and the caudal intraparietal (CIP) area. Neuronal activity was recorded while the animals made perceptual decisions based on judging the tilt of 3D visual patterns. The investigators found that CIP shows higher-order spatial representations and more choice-correlated responses, which support a V3A-to-CIP hierarchy. The researchers also discovered modulation of V3A activity by extraretinal factors, suggesting that V3A might be better characterized as contributing to higher-order behavioral functions rather than low-level visual feature processing. Supported by ORIP (P51OD011106), NEI, NICHD, and NINDS.
Dynamics and Origin of Rebound Viremia in SHIV-Infected Infant Macaques Following Interruption of Long-Term ART
Obregon-Perko et al., JCI Insight. 2021.
https://pubmed.ncbi.nlm.nih.gov/34699383/
Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, virus-targeting T cells were predominantly CD4+, increases in circulating inflammatory and coagulation markers, pulmonary pathologic lesions, and the development of neutralizing antibodies were observed. Collectively, the data suggests PTMs are a valuable model to study COVID-19 pathogenesis and may be useful for testing vaccines and therapeutics. Supported by ORIP (P51OD011104) and NIAID.
Effects of Early Daily Alcohol Exposure on Placental Function and Fetal Growth in a Rhesus Macaque Model
Lo et al., American Journal of Obstetrics and Gynecology. 2021.
https://www.sciencedirect.com/science/article/pii/S0002937821008309?via%3Dihub=
In a rhesus macaque model for chronic prenatal alcohol exposure, daily consumption during early pregnancy significantly diminished placental perfusion at mid to late gestation and significantly decreased the oxygen supply to the fetal vasculature throughout pregnancy. These findings were associated with the presence of microscopic placental infarctions. Although placental adaptations may compensate for early environmental perturbations to fetal growth, placental blood flow and oxygenation were reduced, consistent with the evidence of placental ischemic injury that persisted throughout pregnancy. Supported by ORIP (P51OD011092), NICHD, and NIAAA.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
Tissue-Specific Transcriptional Profiling of Plasmacytoid Dendritic Cells Reveals a Hyperactivated State in Chronic SIV Infection
Lee et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009674
Persistent immune activation is an obstacle to optimal health for people living with HIV. Using RNA sequencing, researchers investigated the immunostimulatory potential of plasmacytoid dendritic cells (pDCs) in chronic SIV infection in rhesus macaques. They observed that pDCs have highly activated profiles in these animals. In contrast, pDCs from SIV-infected sooty mangabeys (natural hosts for SIV) had expression profiles similar to uninfected animals. In chronically infected rhesus macaques, interferon alpha transcripts were readily detected in lymph node-homing pDCs, but not those from blood. Therefore, pDCs are a major producer of type-I interferon in chronic SIV infection and could be a useful immunotherapy target. Supported by ORIP (R24OD010445, P51OD011132, P51OD011092, S10OD026799) and NIAID.
Gut Germinal Center Regeneration and Enhanced Antiviral Immunity by Mesenchymal Stem/Stromal Cells
Weber et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.149033
Researchers investigated the effects of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression in SIV-infected rhesus macaques. MSC treatment heightened virus-specific responses and reduced viral load. Clearance of SIV-positive cells from gut mucosal effector sites was correlated with regeneration of germinal centers, restoration of follicular B cells and T follicular helper cells, and enhanced antigen presentation by viral trapping within the follicular dendritic cell network. These changes were associated with enhanced gene expression for type I/II interferon signaling, B cell proliferation, and interleukin 7. MSC treatment also activated metabolic pathways associated with enhanced immunity and viral reduction. Supported by ORIP (P51OD011107) and NIAID.
In Vitro and In Vivo Functions of SARS-CoV-2 Infection-Enhancing and Neutralizing Antibodies
Li et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.06.021
Antibody-dependent enhancement of infection is a concern for clinical use of antibodies. Researchers isolated neutralizing antibodies against the receptor-binding domain (RBD) or N-terminal domain (NTD) of SARS-CoV-2 spike from COVID-19 patients. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific binding modes. RBD and NTD antibodies mediated both neutralization and infection enhancement in vitro. However, infusion of these antibodies into mice or macaques resulted in suppression of virus replication, demonstrating that antibody-enhanced infection in vitro does not necessarily predict enhanced infection in vivo. RBD-neutralizing antibodies having cross-reactivity against coronaviruses were protective against SARS-CoV-2, the most potent of which was DH1047. Supported by ORIP (P40OD012217, U42OD021458, S10OD018164), NIAID, NCI, NIGMS, and NIH Common Fund.
Neutralizing Antibody Vaccine for Pandemic and Pre-Emergent Coronaviruses
Saunders et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03594-0
SARS-CoV-2 is a new member of the betacoronavirus (beta-CoV) genus, which also includes two common mild beta-CoVs and the life-threatening SARS-CoV-1 and MERS-CoV. Vaccines that elicit protective immunity against SARS-CoV-2 and beta-CoVs that circulate in animals could prevent future pandemics. Researchers designed a novel 24-mer SARS-CoV-2 receptor binding domain-sortase A conjugated nanoparticle vaccine (RBD-scNP). Investigators demonstrated that the immunization of macaques with RBD-scNP, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV, and multiple SARS-CoV-2 variants of concern. This pioneering approach serves as a multimeric protein platform for the further development of generalized anti-beta-CoV vaccines. Supported by ORIP (U42OD021458), NIAID, and NCI.
Combining In Vivo Corneal Confocal Microscopy With Deep Learning-Based Analysis Reveals Sensory Nerve Fiber Loss in Acute Simian Immunodeficiency Virus Infection
McCarron et al., Cornea. 2021.
https://doi.org/10.1097/ICO.0000000000002661
Researchers characterized corneal subbasal nerve plexus features of normal and simian immunodeficiency virus (SIV)-infected pigtail and rhesus macaques using in vivo confocal microscopy and a deep learning approach for automated assessments. Corneal nerve fiber length and fractal dimension measurements did not differ between species, but pigtail macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques. Acute SIV infection induced decreased corneal nerve fiber length and fractal dimension in the pigtail macaque model for HIV. Adapting deep learning analyses to clinical corneal nerve assessments will improve monitoring of small sensory nerve fiber damage in numerous clinical contexts, including HIV. Supported by ORIP (U42OD013117) and NINDS.