Biology subjects

Virgilio, M. C.

Publications and source records attributed to Virgilio, M. C..

3 recordsLinked to original sources

bioRxiv2026

Mechanisms of HIV Latency in Hematopoietic Progenitors: GFI1 as a Key Regulator

Durable control of HIV infection is challenged by persistent latent reservoirs, including hematopoietic stem and progenitor cells (HSPCs), which provide a unique niche for proviral silencing. Mechanisms of HIV latency in HSPCs remain poorly studied. Here, we utilized a dual-reporter HIV (89.6 VT1) and single-cell RNA sequencing to identify host factors governing latency in HSPCs. Transcriptomic profiling revealed elevated expression of several genes in latently infected cells, among them the transcriptional repressor GFI1. Functional studies showed that GFI1 suppresses HIV gene expression by binding a conserved sequence near the primer binding site within the long terminal repeat (LTR). Disruption of GFI1 DNA-binding or corepressor recruitment domains diminished its silencing effect. GFI1 also antagonized Tat and NF-{kappa}B-mediated activation, and reversal of GFI1-mediated suppression was most robust with combined HDAC inhibition and NF-{kappa}B activation. These findings position GFI1 as an important regulator of HIV latency in HSPCs.

microbiology↗

bioRxiv2023

HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages.

HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.

microbiology↗

bioRxiv2020

TLR7 ligation augments haematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling and enhanced differentiation

Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia (AML). Therapies for MDS are lacking, particularly those that impact the early stages of disease. We developed a model of MDS using zebrafish using knockout of Rps14, the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals display dose- and age-dependent abnormalities in haematopoiesis, culminating in bone marrow failure with dysplastic features. We utilized rps14 knockdown to undertake an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7 and TLR8. Imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation. Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del (5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anaemia.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗