Selected Grantee Publications
Assessment of Anti-CD20 Antibody Pre-Treatment for Augmentation of CAR-T Cell Therapy in SIV-Infected Rhesus Macaques
Pampusch et al., Frontiers in Immunology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941136/
Chronic HIV replication occurs primarily within lymphoid follicles, and investigators hypothesized that temporary disruption of these follicles would create space for chimeric antigen receptor (CAR) T cell engraftment and lead to increased abundance and persistence of CAR T cells. They evaluated CAR T cell abundance and persistence in rhesus macaques of both sexes following simian immunodeficiency virus (SIV) infection and antiretroviral therapy suppression. Their results suggest that CAR T cells expanded to a greater extent in the depleted and CAR T cell–treated animals. Further studies are needed to evaluate strategies for engraftment and the persistence of HIV-specific CAR T cells. Supported by ORIP (P51OD011106, P51RR000167), NIAID, and NIDA.
SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059597/
MicroRNAs (miRNAs) are thought to be involved in HIV pathogenesis, but the effect of HIV on the compartmentalization of miRNAs within extracellular particles is unclear. Researchers sequenced the small RNA population of paired EVs and ECs from male rhesus macaques. They showed that extracellular miRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid‑based carriers, with a significant proportion associated with ECs. Further, simian immunodeficiency virus (SIV) infection altered the miRNAome profile of EVs and revealed miR‑128‑3p as a potential target of infection. This work suggests that EV‑ and EC‑associated miRNAs potentially could serve as biomarkers for various diseases. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC)
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053514/
MicroRNAs (miRNAs) have been shown to regulate host response to HIV infection. Previously, investigators proposed that the assortment of extracellular miRNAs into distinct carriers could provide a new dimension to miRNA-based biomarkers. In this follow-up study, the investigators used particle purification liquid chromatography to determine the abundance and compartmentalization of blood plasma extracellular miRNAs into extracellular vesicles and extracellular condensates during simian immunodeficiency virus (SIV) infection in male rhesus macaques. They reported that different treatments—combination ART and Δ9‑THC—impart distinct effects on the enrichment and compartmentalization of extracellular miRNAs. These data suggest that the extracellular miRNA profile in blood plasma is altered following SIV infection. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
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.
Chronic TREM2 Activation Exacerbates Aβ-Associated Tau Seeding and Spreading
Jain et al., Journal of Experimental Medicine. 2023.
Using a mouse model for amyloidosis in which Alzheimer’s Disease (AD)–associated tau is injected into the brain to induce amyloid β (Aβ)–dependent tau seeding/spreading, investigators found that chronic administration of an activating triggering receptor expressed on myeloid cells 2 (TREM2) antibody increases microglial activation of dystrophic neurites surrounding Aβ plaques (NP) but increases NP-tau pathology and neuritic dystrophy without altering Aβ plaque burden. These data suggest that sustained microglial activation through TREM2 that does not result in strong myeloid removal might exacerbate Aβ-induced tau pathology, which could have important clinical implications. Supported by ORIP (S10OD021629) and NIA.
SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19
Beckman et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111573
SARS-CoV-2 causes brain fog and other neurological complications in some patients. It has been unclear whether SARS-CoV-2 infects the brain directly or whether central nervous system sequelae result from systemic inflammatory responses triggered in the periphery. Using a rhesus macaque model, researchers detected SARS-CoV-2 in the olfactory cortex and interconnected regions 7 days after infection, demonstrating that the virus enters the brain through the olfactory nerve. Neuroinflammation and neuronal damage were more severe in elderly monkeys with type 2 diabetes. The researchers found that in aged monkeys, SARS-CoV-2 traveled farther along nerve pathways to regions associated with Alzheimer's disease. Supported by ORIP (P51OD011107) and NIA.
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.
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.
Large Comparative Analyses of Primate Body Site Microbiomes Indicate That the Oral Microbiome Is Unique Among All Body Sites and Conserved Among Nonhuman Primates
Asangba et al., Microbiology Spectrum. 2022.
https://www.doi.org/10.1128/spectrum.01643-21
Microbiomes are critical to host health and disease, but large gaps remain in the understanding of the determinants, coevolution, and variation of microbiomes across body sites and host species. Thus, researchers conducted the largest comparative study of primate microbiomes to date by investigating microbiome community composition at eight distinct body sites in 17 host species. They found that the oral microbiome is unique in exhibiting notable similarity across primate species while being distinct from the microbiomes of all other body sites and host species. This finding suggests conserved oral microbial niche specialization, despite substantial dietary and phylogenetic differences among primates. Supported by ORIP (P51OD010425, P51OD011107, P40OD010965, R01OD010980), NIA, NIAID, and NICHD.
Natural Disaster and Immunological Aging in a Nonhuman Primate
Watowich et al., PNAS. 2022.
https://www.pnas.org/content/119/8/e2121663119
Weather-related disasters can exacerbate existing morbidities and increase mortality risk. Researchers examined Hurricane Maria’s impact on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes and was correlated with age-associated alterations in gene expression, in addition to expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. These findings illuminate that natural disasters might become biologically embedded and contribute to earlier onset of disease and death. Supported by ORIP (P40OD012217), NIA, NIMH.