Biology subjects

Hare, J.

Publications and source records attributed to Hare, J..

6 recordsLinked to original sources

bioRxiv2025

An early functional adaptive NK cell signature drives optimal CD8+ T-cell activation and predicts sustained HIV-1 viral control.

A better understanding of the immune responses associated with future viral control in humans during acute HIV-1 infection (AHI) is critical to inform vaccines and immune-based therapeutics. Natural killer (NK) cells and CD8+ T-cells are pivotal in antiviral defence, yet the dynamics and complementary roles of these effector subsets during AHI with different HIV-1 subtypes remain poorly understood. Access to a unique patient cohort recruited during and post-peak HIV-1 viral load with different HIV-1 subtypes and followed up longitudinally in the absence of antiretroviral therapy up to six years post estimated date of infection (EDI) provided a rare opportunity to fill this knowledge gap. Our data show an early expansion of Fc{varepsilon}R{gamma}-CD57+ NK cells with classical adaptive traits concomitant with an enhanced capacity for antibody-dependent cellular cytotoxicity (ADCC) and reactivity against HIV-1 antigens. This distinctive NK cell profile was more abundant in donors with subtype A infection compared to non-subtype A, partially driven by elevated pro-inflammatory cytokine levels and changes in the epigenetic landscape. The accumulation of adaptive NK cells during the first month of infection contributed to the optimal activation of CD8+ T-cells, promoting virus-specific responses. Notably, individuals with higher levels of Fc{varepsilon}R{gamma}-CD57+ adaptive NK cells during the first month of infection were more likely to exhibit long-term viral control in the absence of ART. These findings underscore the critical role of early, high-magnitude adaptive NK cell responses in CD8+ T-cell activation and subsequent immune control. This work provides novel insights into the correlates of protective immunity against HIV-1 infection, with implications for preventative or therapeutic vaccine strategies aimed at promoting adaptive NK cell responses. One Sentence SummaryEarly expansion of adaptive NK cells during acute HIV-1 infection promotes long-term viral control.

immunology↗

bioRxiv2023

Antibodies generated in vitro and in vivo elucidate design of a thermostable ADDomer COVID-19 nasal nanoparticle vaccine

COVID-19 continues to damage populations, communities and economies worldwide. Vaccines have reduced COVID-19-related hospitalisations and deaths, primarily in developed countries. Persisting infection rates, and highly transmissible SARS-CoV-2 Variants of Concern (VOCs) causing repeat and breakthrough infections, underscore the ongoing need for new treatments to achieve a global solution. Based on ADDomer, a self-assembling protein nanoparticle scaffold, we created ADDoCoV, a thermostable COVID-19 candidate vaccine displaying multiple copies of a SARS-CoV-2 receptor binding motif (RBM)-derived epitope. In vitro generated neutralising nanobodies combined with molecular dynamics (MD) simulations and electron cryo-microscopy (cryo-EM) established authenticity and accessibility of the epitopes displayed. A Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Antibodies generated by immunising mice cross-reacted with VOCs including Delta and Omicron. Our study elucidates nasal administration of ADDomer-based nanoparticles for active and passive immunisation against SARS-CoV-2 and provides a blueprint for designing nanoparticle reagents to combat respiratory viral infections.

biochemistry↗

bioRxiv2022

The Growth Hormone Releasing Hormone Signaling Pathway Governs Cardiomyocyte differentiation in human iPS cells.

Here, we present an O2-independent/HIF-1 (Hypoxia inducible factor-1)-dependent mechanism that regulates developmental and regenerative growth of mammalian cardiomyoblasts. An autocrine feedback mechanism of GH/IGF1/SST (Growth hormone/Insulin-like growth factor 1/Somatostatin) signaling, mediated by GHRH/GHRH-R (Growth hormone-releasing hormone/GHRH-Receptor), is established specifically in NKX2-5 (NK2 Homeobox 5) expressing myocardial cells which affects HIF-1 stability through cAMP (cyclic adenosine monophosphate) or cGMP (cyclic guanosine monophosphate) activity. cAMP-mediated HIF-1 stabilization fuels Warburg metabolism and enhances NKX2-5 expression, limiting the developmental and regenerative growth of cardiomyoblasts. In contrast, cGMP-mediated HIF- 1 inhibition (or knock-out of HIF-1) redirects glycolytically derived citrate toward long-chain saturated fatty acid biosynthesis, leading to enhanced developmental and regenerative growth of cardiomyoblasts. These findings suggest that HIF1-mediated glycolysis serves as a rate-limiting, O2-independent sensor of cardiomyogenesis and that targeting GHRH/GHRH-R signaling could be a therapeutic strategy for regenerating the mammalian heart post-injury. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/478572v3_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@16d3f74org.highwire.dtl.DTLVardef@16115edorg.highwire.dtl.DTLVardef@e68dc7org.highwire.dtl.DTLVardef@660861_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSummary Figure.C_FLOATNO Cardiomyoblast proliferative capacity is regulated by HIF1-mediated metabolic profile, through an NKX2-5 lineage-specific, O2-independent feedback mechanism. (A), HIF-1 is aerobically regulated through the intracellular activation of cAMP and cGMP in response to a GH1/IGF1/SST feedback mechanism, which activates the GHRH/GHRH-R signaling pathway in NKX2-5+ cardiomyoblasts. Stabilized HIF-1 (e.g. by CoCl2) promotes Warburg metabolism and cell cycle exit, whereas knockout or inhibition (e.g. YC-1) of HIF-1 or cAMP (low-dose metformin) promotes de novo fatty acid synthesis and enhances cardiomyoblast proliferation. (B), HIF-1 aerobic stabilization switches the metabolism towards glycolysis and restricts cardiomyoblast proliferation. Contrariwise, knockout of HIF-1 promotes oxidative metabolism in the Krebs cycle rather than lactate synthesis, thus stimulating the proliferative and regenerative capacity of cardiomyoblasts. C_FIG

cell biology↗

bioRxiv2020

Sampling SARS-CoV-2 proteomes for predicted CD8 T-cell epitopes as a tool for understanding immunogenic breadth and rationale vaccine design

Predictive models for vaccine design have become a powerful and necessary resource for the expeditiousness design of vaccines to combat the ongoing SARS-CoV-2 global pandemic. Here we use the power of these predicted models to assess the sequence diversity of circulating SARS-CoV-2 proteomes in the context of an individuals CD8 T-cell immune repertoire to identify potential. defined regions of immunogenicity. Using this approach of expedited and rational CD8 T-cell vaccine design, it may be possible to develop a therapeutic vaccine candidate with the potential for both global and local coverage.

immunology↗

bioRxiv2020

Utilizing Computational Machine Learning Tools to Understand Immunogenic Breadth in the Context of a CD8 T-Cell Mediated HIV Response

Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individuals CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, Analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design that, in combination with in vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.

immunology↗

bioRxiv2019

PDGFRA Defines the Mesenchymal Stem Cell Kaposi’s Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment

Kaposis sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (P(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected P(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected P(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.\n\nAUTHOR SUMMARYIdentification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify P(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the P(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.

cancer biology↗