Selected Grantee Publications
Myeloid Cell Tropism Enables MHC-E–Restricted CD8+ T Cell Priming and Vaccine Efficacy by the RhCMV/SIV Vaccine
Hansen et al., Science Immunology. 2022.
https://www.doi.org/10.1126/sciimmunol.abn9301
Simian immunodeficiency virus (SIV) vaccines based on strain 68-1 rhesus cytomegalovirus vectors have been shown to arrest viral replication early in primary infection. The specific characteristics underlying this effect are not understood fully. In this study, the researchers used host microRNA–mediated vector tropism restriction to demonstrate that the targeted responses are dependent on vector infection of distinct cell types in a rhesus macaque model. Only vectors programmed to elicit major histocompatibility complex E–restricted CD8+ T cell responses provided protection against SIV challenge. These findings could be applied in the development of other vaccines for cancers and infectious diseases. Supported by ORIP (P51OD011092), NCI, and NIAID.
A Cellular Trafficking Signal in the SIV Envelope Protein Cytoplasmic Domain Is Strongly Selected for in Pathogenic Infection
Lawrence et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1010507
Envelope glycoproteins within the cytoplasmic domain of HIV and simian immunodeficiency virus (SIV) include a tyrosine-based motif that mediates endocytosis and polarized sorting in infected cells. Mutation of this tracking signal has been shown to lead to suppressed viral replication and failed systemic immune activation, but the mechanism has not been explored fully. Using rhesus and pigtail macaque models, the researchers demonstrated that molecular clones containing the mutations reconstitute signals for both endocytosis and polarized sorting. Their findings suggest strong selection pressure for these processes during pathogenic HIV and SIV infection. Supported by ORIP (P51OD011104), NCI, and NIAID.
Early Post-Vaccination Gene Signatures Correlate With the Magnitude and Function of Vaccine-Induced HIV Envelope–Specific Plasma Antibodies in Infant Rhesus Macaques
Vijayan et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.840976
An effective vaccine is needed to reduce HIV infections, particularly among younger people. The initiation of an HIV vaccine regimen in early life could allow the development of mature HIV‑specific antibody responses that protect against infection. The investigators compared the effects of two vaccine regimens in infant rhesus macaques (sex not specified). Both vaccines induced a rapid innate response, indicated by elevated inflammatory plasma cytokines and altered gene expression. By performing a network analysis, the investigators identified differentially expressed genes associated with B cell activation. These findings suggest that vaccine-induced immunity can be optimized by modulating specific antibody and T cell responses. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.
Vaccine-Induced, High-Magnitude HIV Env-Specific Antibodies with Fc-Mediated Effector Functions Are Insufficient to Protect Infant Rhesus Macaques against Oral SHIV Infection
Curtis et al., mSphere. 2022.
https://www.doi.org/10.1128/msphere.00839-21
A tailored, effective HIV vaccine is needed to prevent mother-to-child viral transmission. In nonhuman primate models, infection with simian–human immunodeficiency virus (SHIV) can be prevented by administering broadly neutralizing HIV envelope (Env)–specific antibodies. Investigators tested the efficacy of an intramuscular vaccine regimen against SHIV infection in male and female infant rhesus macaques. The vaccine induced Env-specific antibodies in plasma, with antibody-dependent cellular cytotoxicity and phagocytic function. These antibodies, however, were insufficient for protection against infection. Future studies could focus on improving the breadth of antibody response and improving cell-mediated immunity. Supported by ORIP (P51OD011107), NCI, NIAID, and NIDCR.
Functional and Ultrastructural Analysis of Reafferent Mechanosensation in Larval Zebrafish
Odstrcil et al., Current Biology. 2022.
https://www.sciencedirect.com/science/article/pii/S096098222101530X
All animals need to differentiate between exafferent stimuli (caused by the environment) and reafferent stimuli (caused by their own movement). Researchers characterized how hair cells in zebrafish larvae discriminate between reafferent and exafferent signals. Dye labeling of the lateral line nerve and functional imaging was combined with ultra-structural electron microscopy circuit reconstruction to show that cholinergic signals originating from the hindbrain transmit efference copies, and dopaminergic signals from the hypothalamus may affect threshold modulation. Findings suggest that this circuit is the core implementation of mechanosensory reafferent suppression in these young animals. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy
Solis-Leal et al., Viruses. 2022.
https://www.doi.org/10.3390/v14010139
The central nervous system (CNS) HIV reservoir contributes to residual neuroimmune activation, which can lead to HIV-associated neurocognitive disorder. Researchers characterized the expression of signaling molecules associated with inflammation in plasma, cerebrospinal fluid, and basal ganglia of Chinese-origin rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV). They reported a correlation between levels of CCL2 in plasma and cerebrospinal fluid, suggesting that researchers could infer the degree of CNS inflammation by testing CCL2 levels in peripheral blood. Overall, these findings provide insight into neuroinflammation and signaling associated with HIV persistence in the CNS. Supported by ORIP (P51OD011104, P51OD011133), NIMH, and NINDS.
AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
Goertsen et al., Nature Neuroscience. 2021.
https://www.nature.com/articles/s41593-021-00969-4
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.
Precise Visuomotor Transformations Underlying Collective Behavior in Larval Zebrafish
Harpaz et al., Nature Communications. 2021.
https://www.nature.com/articles/s41467-021-26748-0
Sensory signals from neighbors, analyzed in the visuomotor stream of animals, is poorly understood. The authors studied aggregation behavior in larval zebrafish and found that over development larvae transition from over dispersed groups to tight shoals. Young larvae turn away from virtual neighbors by integrating and averaging retina-wide visual occupancy within each eye, and by using a winner-take-all strategy for binocular integration. Observed algorithms accurately predict group structure over development. These findings allow testable predictions regarding the neuronal circuits underlying collective behavior in zebrafish. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.
Collective Behavior Emerges from Genetically Controlled Simple Behavioral Motifs in Zebrafish
Harpaz et al., Science Advances. 2021.
https://www.science.org/doi/10.1126/sciadv.abi7460
Harpaz et al. report that zebrafish regulate their proximity and alignment with each other at early larval stages. Two visual responses (one measuring relative visual field occupancy and one accounting for global visual motion), account for emerging group behavior. Mutations in genes known to affect social behavior in humans perturb these reflexes in individual larval zebrafish and change their emergent collective behaviors. Model simulations show that changes in these two responses in individual mutant animals predict well the distinctive collective patterns that emerge in a group. Hence, group behaviors reflect in part genetically defined primitive sensorimotor “motifs” evident in young larvae. Supported by ORIP (R43OD024879, R44OD024879) and NINDS.