Cheema, K. | bioRxiv Science

bioRxiv2026

Loss of Vpr-driven TRAIL-R2 expression protects HIV-infected cells from non-canonical NK cell TRAIL attack

HIV escapes sterilizing immunity through a variety of mechanisms, including the downregulation of MHC-I expression by HIV Nef and Vpu to counteract CD8+ T cell responses. While reduced MHC-I expression would be expected to support targeting by NK cells, a subpopulation of infected CD4+ T cells consistently resists multiple rounds of NK cell natural and antibody-dependent cytotoxicity. Studies further reveal that the HIV accessory protein Vpr induces expression of TNFRSF10B (TRAIL-R2) in CD4+ T cells, with survivors of NK cell targeting exhibiting relatively higher MHC-I and weaker expression of TRAIL-R2. In fact, reverse TRAIL signaling in NK cells leads to the release of perforin and granzymes, a pathway limited when TRAIL-R2 expression is diminished. Thus, independent of canonical death receptor signaling, TRAIL-R2 serves as an activating ligand that augments NK cell killing. These observations demonstrate that through Vpr, HIV can regulate the TRAIL/TRAIL-R2 axis to control NK cell functionality.

immunology↗

bioRxiv2025

A Porcine Model of Intervertebral Disc Injury Recapitulates Human Discogenic Pain via Notochordal Cell Loss and Pain-inducing Nucleus Pulposus Cell Emergence

Lower back pain (LBP) is one of the most common causes of disability, with up to 40% of LBP cases attributed to intervertebral disc (IVD) degeneration. While small animal models are widely used to study IVD and LBP, the small size of their IVDs limits translational and biological relevance. Large animal models more accurately emulate human disease; however, methods of measuring LBP are not well established. Pigs were also considered unfit for LBP research, due to notochordal cells (NCs) persistence through life, unlike humans. We developed a comprehensive porcine model with quantitative measure of discogenic pain via biobehavioral testing (BBT), MRI, and multi-omics tissue analysis of IVD and DRGs. MRI demonstrated the progression of IVD degeneration beginning at 4 weeks post-injury. BBTs showed the development of significant pain responses by week 4 post-injury, supported by transcriptomics of injury matched DRGs. Single cell transcriptomics, trajectory and cell-cell communication analyses suggest that, with injury, NCs are differentiating to nucleus pulposus cells (NPCs). Furthermore, NPCs showed upregulation of cellular stress, neural outgrowth, and inflammation pathway, consistent with pain-inducing distress signals found in human samples. This study establishes novel MRI and BBT-based methods for quantifying LBP in pigs and supports its translational relevance to human discogenic LBP. The identification of LBP-associated clusters mirrors our previous finding in humans. Moreover, the shift of NC to NPC phenotype further supports that the porcine model is relevant to human pathology, as the injury induced accelerated aging and loss of NCs with IVD degeneration and discogenic pain.

developmental biology↗