Selected Grantee Publications
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- 14 results found
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- Immunology
- 2023
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
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
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.
Identification of an Anergic BND Cell–Derived Activated B Cell Population (BND2) in Young-Onset Type 1 Diabetes Patients
Stensland et al., The Journal of Experimental Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/37184563/
B cells have been shown to play a role in the pathogenesis of type 1 diabetes (T1D), but the specificity, phenotype, and function of B cells in young-onset T1D is not understood fully. The investigators performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of male and female T1D patients and control participants using mass cytometry. They found elevated insulin-reactive BND2 cells in the blood and pancreatic lymph nodes of young-onset T1D donors. This work suggests that an antigen-specific B cell subset could contribute to the rapid progression of young-onset T1D. Supported by ORIP (K01OD028759) and NIDDK.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
CD8+ T Cells Promote HIV Latency by Remodeling CD4+ T Cell Metabolism to Enhance Their Survival, Quiescence, and Stemness
Mutascio et al., Immunity. 2023.
https://www.doi.org/10.1016/j.immuni.2023.03.010
An HIV reservoir persists following antiretroviral therapy, representing the main barrier to an HIV cure. Using a validated in vitro model, investigators explored the mechanism by which CD8+ T cells promote HIV latency and inhibit latency reversal in HIV-infected CD4+ T cells. They reported that CD8+ T cells favor the establishment of HIV latency by modulating metabolic, stemness, and survival pathways that correlate with the downregulation of HIV expression and promote HIV latency. In future studies, comparative analyses may provide insight into common molecular mechanisms in the silencing of HIV expression by CD8+ T cells and macrophages, which can be applied to new intervention strategies that target the HIV reservoir. Supported by ORIP (P51OD011132, S10OD026799), NIAID, NIDDK, NIDA, NHLBI, and NINDS.
Hematopoietic Stem Cells Preferentially Traffic Misfolded Proteins to Aggresomes and Depend on Aggrephagy to Maintain Protein Homeostasis
Chua et al., Cell Stem Cell. 2023.
https://pubmed.ncbi.nlm.nih.gov/36948186/
Investigators studied the mechanism of hematopoietic stem cells (HSCs) being dependent on managing proteostasis. Their findings demonstrated that HSCs preferentially depend on aggrephagy, a form of autophagy, to maintain proteostasis. When aggrephagy is disabled, HSCs compensate by increasing proteasome activity, but proteostasis is ultimately disrupted as protein aggregates accumulate and HSC function is impaired. The investigators also showed that Bag3 deficiency blunts aggresome formation in HSCs, resulting in protein aggregate accumulation, myeloid-biased differentiation, and diminished self-renewal activity, thus demonstrating Bag3 as a regulator of HSC proteostasis. HSC aging is associated with loss of aggresomes and reduced autophagic flux. Protein degradation pathways are thus configured in young-adult HSCs to preserve proteostasis and fitness but become dysregulated during aging. Supported by ORIP (S10OD032316, S10OD021831), NCI, and NIDDK.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.