Selected Grantee Publications
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- 312 results found
- Immunology
- Stem Cells/Regenerative Medicine
High Throughput Analysis of B Cell Dynamics and Neutralizing Antibody Development During Immunization With a Novel Clade C HIV-1 Envelope
Mopuri et al., PLoS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10627474/
Broadly neutralizing antibodies from chronic infection are an area of interest for HIV-1 vaccine development. Using male and female rhesus macaques, a team of researchers conducted a high-throughput longitudinal study to determine how B cells respond to vaccines expressing different HIV-1 Env immunogens. In most animals, the B cells failed to achieve neutralizing activity. One animal, however, developed neutralizing antibodies against the vaccine strain. These data suggest that early elicitation might favor the induction of neutralizing antibodies against HIV-1 Env. This work offers new insights for autologous neutralizing antibody lineages. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
Interferon Regulatory Factor 7 Modulates Virus Clearance and Immune Responses to Alphavirus Encephalomyelitis
Troisi et al., Journal of Virology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37772825/
Interferon regulatory factor 7 (IRF7)–deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7-/- mice produce low levels of IFN-α but high levels of IFN-β with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7-/- mice developed inflammation earlier but failed to clear virus from motor neuron–rich regions of the brainstem and spinal cord. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance. Supported by ORIP (T32OD011089, R01OD01026529) NINDS, and NIAID.
CD8+ T Cells Control SIV Infection Using Both Cytolytic Effects and Non-Cytolytic Suppression of Virus Production
Policicchio et al., Nature Communications. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10589330/
HIV continuously evades and subdues the host immune responses through multiple strategies, and an understanding of these strategies can help inform research efforts. Using a mathematical model, investigators assessed whether CD8+ cells from male rhesus macaques exert a cytolytic response against infected cells prior to viral production. Their goal was to elucidate the possible mode of action of CD8+ cells on simian immunodeficiency virus (SIV)–infected cells. Models that included non‑cytolytic reduction of viral production best explained the viral profiles across all macaques, but some of the best models also included cytolytic mechanisms. These results suggest that viral control is best explained by the combination of cytolytic and non-cytolytic effects. Supported by ORIP (P40OD028116, R01OD011095), NIAID, NIDDK, and NHLBI.
Timing of Initiation of Anti-Retroviral Therapy Predicts Post-Treatment Control of SIV Replication
Pinkevych et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558076/
Researchers are interested in approaches to reducing viral rebound following interruption of antiretroviral therapy, but more work is needed to understand major factors that determine the viral “setpoint” level. Researchers previously assessed how timing of treatment can affect the frequency of rebound from latency. In the current study, the authors analyzed data from multiple studies of simian immunodeficiency virus (SIV) infection in rhesus macaques to further explore the dynamics and predictors of post-treatment viral control. They determined that the timing of treatment initiation was a major predictor of both the level and the duration of post-rebound SIV control. These findings could help inform future treatments. Supported by ORIP (U42OD011023, P51OD011132, P51OD011092), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS
AZD5582 Plus SIV-Specific Antibodies Reduce Lymph Node Viral Reservoirs in Antiretroviral Therapy–Suppressed Macaques
Dashti et al., Nature Medicine. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579098/
Researchers are interested in targeting the HIV reservoir via a latency reversal and clearance approach. Previously, investigators demonstrated that AZD5582 induces systemic latency reversal in rhesus macaques and humanized mice, but a consistent reduction in the viral reservoir was not observed. In the current study, they combined AZD5582 with four simian immunodeficiency virus (SIV)–specific rhesus monoclonal antibodies using rhesus macaques of both sexes. They reported a reduction in total and replication-competent SIV DNA in lymph node–derived CD4+ T cells in the treated macaques. These findings provide proof of concept for the potential of the latency reversal and clearance HIV cure strategy. Supported by ORIP (P51OD011132, R01OD011095), NIAID, NCI, and NHLBI.
Biphasic Decay of Intact SHIV Genomes Following Initiation of Antiretroviral Therapy Complicates Analysis of Interventions Targeting the Reservoir
Kumar et al., PNAS. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614214/
The latent HIV-1 reservoir persists with antiretroviral therapy (ART), and assays for quantifying intact proviruses in nonhuman primate models are needed. Researchers used a simian–human immunodeficiency virus (SHIV) intact proviral DNA assay to describe viral decay during the first year of ART in female rhesus macaques. Their results suggest that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase and a slower second phase. These findings can provide insight for future studies using SHIV models, as well as new cure interventions. Supported by ORIP (R01OD011095) and NIAID.
Increased Collective Migration Correlates With Germline Stem Cell Competition in a Basal Chordate
Fentress and De Tomaso et al., PLOS One. 2023.
https://pubmed.ncbi.nlm.nih.gov/37903140/
Cell competition is a process that compares the relative fitness of progenitor cells and results in healthier cells, contributing a higher proportion to the final tissue composition. Investigators are studying cell competition in a novel model organism, the colonial ascidian, Botryllus schlosseri. They demonstrated that winner germline stem cells show enhanced migratory ability to chemotactic cues ex vivo and that enhanced migration correlates with both expression of the Notch ligand, Jagged, and cluster size. The ability to study conserved aspects of cell migration makes Botryllus an excellent model for future studies on competition, chemotaxis, and collective cell migration. Supported by ORIP (R21OD030520) and NIGMS.
First-in-Human ImmunoPET Imaging of COVID-19 Convalescent Patients Using Dynamic Total-Body PET and a CD8-Targeted Minibody
Omidvari et al., Science Advances. 2023.
https://pubmed.ncbi.nlm.nih.gov/36993568/
Developing noninvasive methods for in vivo quantification of T cell distribution and kinetics is important because most T cells reside in the tissue. Investigators presented the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell distribution in healthy individuals and COVID-19 patients. Kinetic modeling results aligned with the expected T cell trafficking effects. Tissue-to-blood ratios were consistent with modeled net influx rates and flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory. Supported by ORIP (S10OD018223) and NCI.
The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid
Jordan et al., Journal of Immunology. 2023.
Bullous pemphigoid is associated with eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies. Researchers previously established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice. In this study, they characterized the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury. Their work establishes the eotaxin-1/CCR3 axis and matrix metalloproteinase-9 as key players in the disease and as candidate therapeutic targets for drug development and testing. Supported by ORIP (T32OD011130) and NIAMS.
Enhanced IL-17 Producing and Maintained Cytolytic Effector Functions of Gut Mucosal CD161+ CD8+ T Cells in SIV-Infected Rhesus Macaques
Thirugnanam et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535321/
HIV infection is associated with the depletion of CD161-expressing CD4+ Th17 cells, but the effects on other IL-17–producing T cell subsets are not understood fully. Researchers characterized the functions of non-invariant CD161-expressing CD8+ T cell subpopulations in peripheral blood and mucosal tissues of rhesus macaques (sex not specified) during chronic simian immunodeficiency virus (SIV) infection. They demonstrated that cell frequencies and function were unaffected by infection, but enhanced IL-17 production capacity and sustained Th1-type and cytolytic functions were observed. This work suggests that CD161-expressing CD8+ T cells might have important functions in gut mucosal immunity during chronic HIV infection. Supported by ORIP (P51OD011104, S10OD026800), NIAID, NIDDK, and NIMH.