Biology subjects

Pade, C.

Publications and source records attributed to Pade, C..

4 recordsLinked to original sources

bioRxiv2026

HIV-1 Vpr counteracts TASOR restriction to promote infection prior to integration

HIV-1 is challenged by many intrinsic antiviral factors including APOBEC3G, Tetherin/BST-2 and SERINC5 which are overcome by viral accessory proteins Vif, Vpu and Nef respectively. HIV-1 Vpr has multiple proposed cellular targets including REAF, previously shown by us to restrict early after virus entry, but its function is incompletely understood. TASOR is a component of HuSH, an epigenetic silencing complex which inhibits expression of HIV-1 and is overcome by HIV-2/SIV Vpx. We report that TASOR, in addition to silencing integrated provirus, inhibits viral replication prior to integration during reverse transcription. TASOR impairs viral replication in primary macrophages and restriction of a primary isolate is also shown. The restriction to replication is overcome by HIV-1 Vpr which induces TASOR degradation concomitant with reverse transcription. Using Vpr mutants Q65R and F34I we show that interaction with the CRL4-DCAF1 E3 ligase and nuclear localisation are required for Vpr to mitigate TASOR. The pre and post integration mechanism of Vpr mediated TASOR mitigation is genetically segregated using cell cycle Vpr mutant R80A. TASOR depletion induces cells to accumulate in G2/M and arrested cells are more susceptible to HIV-1. Understanding the mechanistic details of pathogen-host interactions is critical for the design of effective anti-HIV/AIDS therapeutics.

immunology↗

bioRxiv2025

HIV-1 Vpr alters cellular transcription by targeting the PAF1 complex

Innate immunity represents the first line of defence against viral infections, and successful pathogens like HIV-1 have evolved mechanisms to bypass these barriers. The PAF1 complex (PAF1c) has emerged as a key regulator of antiviral innate immune responses, inhibiting the replication of various viruses, including HIV-1. While its role in transcription regulation is well documented, little is known about how PAF1c inhibits HIV-1 and how HIV-1 circumvents this antiviral activity. Here we demonstrate that Vpr induces the rapid and transient downmodulation of PAF1c shortly after infection, a process that correlates with significant transcriptomic changes within the host cell. Transcriptomic profiling reveals that PAF1 knockdown mirrors many of the gene expression changes induced by HIV-1 infection, indicating that Vpr antagonism of PAF1c is a means by which HIV-1 may modulate host gene expression to favour replication. Further, we show that the loss of PAF1c leads to the suppression of interferon-stimulated genes (ISGs) and several known HIV-1 restriction factors. Overall, the evidence supports the emerging role of PAF1 as a regulator of a broad antiviral transcriptional program, but also suggests a specific anti-HIV activity that is countered by HIV-1 Vpr.

microbiology↗

bioRxiv2024

Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1

Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface. ELC07 binds the closed state of the viral glycoprotein causing considerable perturbations to the gp41 trimer core structure. Phenotypic analysis of memory B cell subsets from the ELC07 bnAb donor revealed a lack of expected HIV-1-associated dysfunction, specifically no increase in CD21-/CD27- cells was observed whilst the resting memory (CD21+/CD27+) population appeared preserved despite uncontrolled HIV-1 viraemia. Moreover, single cell transcriptomes of memory B cells from this bnAb donor showed a resting memory phenotype irrespective of the epitope they targeted or their ability to neutralise diverse strains of HIV-1. Strikingly, single memory B cells from the ELC07 bnAb donor were transcriptionally similar to memory B cells from HIV-negative individuals. Our results demonstrate that potent bnAbs can arise without the HIV-1-induced dysregulation of the memory B cell compartment and suggest that sufficient levels of antigenic stimulation with a strategically designed immunogen could be effective in HIV-negative vaccine recipients.

microbiology↗

bioRxiv2022

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naive repertoire. High frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection. One-Sentence SummaryHigh frequency naive precursors underly the rapid T cell response during the crucial early phases of acute viral infection.

immunology↗