Selected Grantee Publications
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
Isoniazid and Rifapentine Treatment Effectively Reduces Persistent M. tuberculosis Infection in Macaque Lungs
Sharan et al., Journal of Clinical Investigation. 2022.
https://www.doi.org/10.1172/JCI161564
People with HIV and asymptomatic latent tuberculosis (TB) coinfection are at risk of developing active TB symptoms. The Centers for Disease Control and Prevention recommends a weekly dose of isoniazid and rifapentine for 3 months (3HP) for treatment of latent TB infection, but the sterilizing efficacy of the regimen has not been demonstrated previously. Using rhesus macaques of both sexes, researchers evaluated the efficacy of the 3HP regimen in eradicating persistent Mycobacterium tuberculosis infection. They found that treatment reduced the risk of developing active TB but did not establish complete sterilization. This work establishes a new animal model for evaluating the efficacy of different drug regimens. Supported by ORIP (P51OD011133, S10OD028732).
A Molecularly Integrated Amygdalo-Fronto-Striatal Network Coordinates Flexible Learning and Memory
Li et al., Nature Neuroscience. 2022.
https://www.doi.org/10.1038/s41593-022-01148-9
Behavioral flexibility is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors, but the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory are not understood fully. Using a mouse model, researchers demonstrated that the OFC neuronal ensembles store a memory trace for newly learned information. They describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time. Supported by ORIP (P51OD011132), NIDA, NIMH, and NINDS.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.
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.
Durable Protection Against the SARS-CoV-2 Omicron Variant Is Induced by an Adjuvanted Subunit Vaccine
Arunachalam et al., Science Translational Medicine. 2022.
https://www.doi.org/10.1126/scitranslmed.abq4130
Additional SARS-CoV-2 vaccines are needed, owing to waning immunity to the original vaccines and the emergence of variants of concern. A recent study in male rhesus macaques demonstrated durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, an oil-in-water emulsion containing α‑tocopherol. Two immunizations with the vaccine resulted in durable immunity, without cross-reactivity. Further boosting with a version of the vaccine containing the Beta variant or the ancestral RBD elicited cross-reactive immune responses that conferred protection against Omicron challenge. Supported by ORIP (P51OD011104), NCI, and NIAID.
Neuroprotective Effects of Electrical Stimulation Following Ischemic Stroke in Non-Human Primates
Zhou et al., Institute of Electrical and Electronics Engineers. 2022.
https://www.doi.org/10.1109/EMBC48229.2022.9871335
Using rhesus macaques of both sexes, researchers identified a novel treatment for ischemic stroke, which occurs when brain cells die due to lack of oxygen. The treatment consisted of applying 60 minutes of electrical brain stimulation shortly after the stroke. The animals that received electrical stimulation had less brain damage, fewer cell deaths, and more protective neural activity patterns than the monkeys that did not receive electrical stimulation. Future work can determine whether this stimulation can be applied noninvasively, as well as how to improve the electrical stimulation patterns to optimize health outcomes for stroke patients. Supported by ORIP (P51OD010425) and NINDS.
A Clade C HIV-1 Vaccine Protects Against Heterologous SHIV Infection by Modulating IgG Glycosylation and T Helper Response in Macaques
Sahoo et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abl4102
Vaccines for HIV-1 capable of generating a broadly cross-reactive neutralizing antibody response are needed urgently. The researchers tested the protective efficacy of a clade C HIV-1 vaccination regimen in male rhesus macaques. The vaccine was administered either orally using a needle-free injector or via parenteral injection. Significant protection was observed for both vaccination routes following the simian–human immunodeficiency virus (SHIV) challenge, with an estimated efficacy of 68% per exposure. The glycosylation profile of IgG and HIV-resistant helper T cell response contributes to the protection. Supported by ORIP (P51OD011132), NIAID, and NIDCR.
Allogeneic MHC‑Matched T‑Cell Receptor Α/Β‑Depleted Bone Marrow Transplants in SHIV‑Infected, ART‑Suppressed Mauritian Cynomolgus Macaques
Weinfurter et al., Scientific Reports. 2022.
https://www.doi.org/10.1038/s41598-022-16306-z
Allogeneic hematopoietic stem cell transplants are effective in reducing HIV reservoirs following antiretroviral therapy (ART). A better understanding of this mechanism could enable the development of safer and more efficacious HIV treatment regimens. In this study, the researchers used a Mauritian cynomolgus macaque model to study the effects of allogeneic major histocompatibility complex–matched α/β T cell–depleted bone marrow cell transplantation following infection with simian–human immunodeficiency virus (SHIV). The macaques began ART 6 to 16 weeks post-infection. In three of the four macaques, SHIV DNA was undetectable in blood but persisted in other tissues. These results suggest that extended ART likely is needed to eradicate the HIV reservoir following transplantation. In future studies, full donor engraftment should be balanced with suppression of graft-versus-host disease. Supported by ORIP (P51OD011106, R24OD021322), and NCI.
Innate Immune Regulation in HIV Latency Models
Olson et al., Retrovirology. 2022.
https://www.doi.org/10.1186/s12977-022-00599-z
Researchers are interested in developing therapeutic approaches to target latent HIV reservoirs, which are unaffected by antiretroviral therapy. Previous studies suggest that HIV latency might be related to viral RNA sensing, interferon (IFN) signaling, and IFN-stimulated gene (ISG) activation. In this study, the researchers evaluated responses to stimulation by retinoic acid–inducible gene I agonists and IFN in multiple CD4+ T cell line models for HIV latency. The models represented various aspects of latent infection and viral control. Several of the cell lines demonstrated reduced ISG induction, suggesting that long-term latency might be related to dysregulation of the downstream IFN response. These effects likely reflect transcriptional changes occurring within a core set of ISGs and altering IFN responses. Additional studies could provide insight into the functions of these ISGs in HIV latency. Supported by ORIP (P51OD010425), NCATS, and NIAID.