Virology Research Techniques

A new study from Northwestern Medicine, published in Nature Communications, uncovers a previously unrecognized way #HIV evades the #immunesystem and points to a promising new therapeutic strategy. ▪️ Led by Dr. Mohamed Abdel-Mohsen, PhD, Margaret Gray Morton Professor of Medicine in the Division of Infectious Diseases at Northwestern University, the research shows that HIV-infected cells reprogram their surface sugars (sialoglycans) to engage inhibitory Siglec receptors (including Siglec-3, -7, -9, and -10) on #immunecells. These act as “glyco-immune checkpoints,” effectively cloaking infected cells from immune attack. 🔬 What this study adds to what we know: While #antiretroviraltherapy (#ART) suppresses viral replication, HIV persists because infected cells escape #immune surveillance. This study provides mechanistic insight into how that escape happens - identifying sugar–Siglec interactions as a key immune evasion pathway. The team also demonstrates a novel therapeutic concept: an engineered HIV-targeting antibody linked to sialidase, designed to strip away the protective sugars and restore immune-mediated killing. In cell models and mice, this approach enhanced immune clearance, reduced viral load, and lowered #inflammation. 🌍 Why it matters: Beyond HIV, this work highlights a broader #immunology principle: sugar-based immune evasion mechanisms seen in viral #infection mirror those described in #cancer, opening new avenues for cross-disciplinary therapeutic strategies. The team’s next step is to test this approach in ART-treated models, moving closer to the goal of a functional cure - sustained HIV remission without lifelong therapy. Dr. Abdel-Mohsen is also a member of the ROBERT H. LURIE COMPREHENSIVE CANCER CENTER OF NORTHWESTERN UNIVERSITY. 🗃️ See comments for reference.

SARS-CoV-2 may evade immune responses by inducing unproductive antiviral response proteins In a paper published today, we collaborated with Gloria Franco's lab to demonstrate that the interferon-stimulated genes activated during viral infection most likely do not produce functional proteins. This also applies to class I MHC genes, which encode proteins essential for alerting the immune system to virally infected cells. Consequently, antiviral responses are likely to be impaired at the translational level. We propose that SARS-CoV-2 employs a previously unreported strategy of manipulating the host's splicing machinery to enhance viral replication and evade the immune response. This is achieved by selectively upregulating unproductive splicing isoforms of genes involved in antigen presentation and antiviral defense. Congrats: Gloria Franco Thomaz Lüscher Dias, PhD Izabela Mamede Ícaro Castro Rafael Polidoro

The Lineage IV Lassa virus glycoprotein, particularly the Josiah strain, plays a critical role in the virus's ability to infect host cells and initiate disease. Structurally, the glycoprotein complex (GPC) is synthesized as a single polypeptide precursor (pre-GP), which undergoes post-translational cleavage by host proteases. The primary function of the Lassa virus glycoprotein is to mediate viral entry into host cells, which involves two critical steps: receptor binding and membrane fusion. GP1 is responsible for the initial binding to the host cell receptor, α-DG. However, this interaction is complex and heavily influenced by the glycosylation pattern of the host receptor. Once the virus attaches to the host cell, it is endocytosed into the host cell via clathrin-mediated endocytosis. Upon acidification within the endosome, the GP2 subunit undergoes a conformational change, exposing its hydrophobic fusion peptide. This conformational change allows the GP2 fusion peptide to insert into the host cell membrane, facilitating the merging of the viral and host membranes. The Lassa virus glycoprotein also plays a significant role in immune evasion. The extensive glycan shield on the glycoprotein surface masks critical antigenic sites, reducing the efficacy of host antibodies in recognizing and neutralizing the virus. Understanding the structural and functional nuances of the glycoprotein offers valuable insights for therapeutic interventions, including vaccine development and the design of neutralizing antibodies Here you can see a cryoEM structure of the lineage IV Lassa virus glycoprotein (Josiah) in complex with rabbit polyclonal antibody (GPC-C epitope) (PDB code: 8VCV) #molecularart #virus #lassa #membrane #glycoprotein #entry #immuneresponse #cryoem Structure rendered with 3D Protein Imaging, post-processed with Dzine (formerly Stylar AI) and depicted with @corelphotopaint

RNA N-glycosylation enables immune evasion and homeostatic efferocytosis by chemically caging acp3U. Excited to report this work lead by Vincent Graziano and in collaboration with Vijay Rathinam in Nature Magazine  https://lnkd.in/erHGJ_iN We found that de-N-glycosylation of purified small RNA using PNGaseF causes the RNA to be immunostimulatory to both mouse and human macrophages. This effect was also true on the surface of apoptotic material which is normally cleared via efferocytosis in an immune silent process. Loss of N-glycans on this material triggers innate immune cells. We defined the chemical moiety causing this stimulation to be the core RNA modification of acp3U, which we had previously found to be a covalent linker between RNA and N-glycans (Xie et al. Cell 2024). We confirmed this with chemical synthesis RNAs containing only 1 acp3U. Finally, we found that the de-N-glycosylated RNA is sensed through both TLR3 and TLR7 which could suggest that encoding both ssRNA and dsRNA motifs with acp3U and thus dual engagement of TLR3 and TLR7 provides sufficient signal threshold. The work brought together a lot of expertise from labs including Penghua Wang Michael Wilson Sivapriya Kailasan Vanaja, Beiyan Zhou Franck Barrat Thomas Carell - and we were critically supported by grants from NIH (NIGMS, NIAID, NIDDK) and Scleroderma Research Foundation

You’re ready for more? #ItsNotACold Summary by Zdenek Vrozina: ”A new review breaks down what SARS-CoV-2 ORF/accessory proteins actually do - from interferon suppression to mitochondrial disruption. Here are the key points, followed by how some of these mechanisms compare to those used by HIV. This new review makes something very clear. SARS-CoV-2 doesn’t rely only on spike. It uses a broad arsenal of accessory proteins (APs) that shape how severe the acute phase becomes, which organs are affected, and the biological conditions that make long-term sequelae more likely. These proteins aren’t side notes - they’re central modules of pathogenesis. The review goes protein by protein and shows a pattern we haven’t had clearly assembled before. SARS-CoV-2 runs a multi-layer immune-evasion network. Total interferon shutdown, secondary inflammatory escalation, mitochondrial disruption, antigen-presentation interference, and the capacity to persist inside tissue compartments. Each layer has a defined mechanism. Interferon is shut down at every critical node. The virus doesn’t use one trick - it uses all of them. ORF3a - suppresses STAT1 phosphorylation ORF3c / ORF10 - degrade MAVS ORF6 - blocks IRF3/STAT1/STAT2 from entering the nucleus ORF7a/7b - disrupt downstream IFN signaling ORF8 - interferes with ER chaperones ORF9b - blocks TOM70 - TBK1 never activates Result: early immune paralysis. After IFN collapse, the viral proteins flip the switch to inflammation Several APs ignite strong inflammatory pathways. ORF3a - NF-κB + NLRP3 inflammasome ORF7a - IL-6, IL-1β, TNF ORF8 - IL-17-like activation ORF9b - inflammasome activation in specific cells The classic COVID pattern. Silent phase - inflammatory explosion. Mitochondria are a primary battlefield. Arguably the strongest piece of the review. ORF3a - loss of cristae, ROS burst, HIF-1α stabilization, autophagy block ORF3c - shift to fatty acid oxidation + lysosomal dysfunction ORF9b/9c/10 - collapse of OXPHOS with no compensatory pathway This is the mechanical foundation for systemic symptoms and LC - COVID as a mitochondria targeting disease. APs can persist inside tissues. According to the review, accessory proteins may remain in the ER, mitochondria, autophagic vesicles, even after viral RNA is no longer detectable. They can maintain low-grade inflammation, HIF-1α activation, metabolic dysfunction. A mechanistic bridge between acute COVID and Long COVID. Omicron may have become milder because key accessory proteins mutated - not because of spike alone. ORF6 D61L - weaker IFN blockade ORF3a T223I - reduced replication ORF9b mutations - less effective IFN antagonism ORF7b changes - impaired oligomerization Accessory proteins act as the gearbox of virulence.” (Cont’d in comments) #SARSCoV2 #ImmunityTheft #ImmuneDysregulation #mitochondria #coronavirus #PublicHealth #Covid19 #LongCovid #postcovid #pandemic https://lnkd.in/dSB5pAFn

🟥 Engineered Viral Vectors with Reduced Immunogenicity and Enhanced Targeting Viral vectors remain one of the most effective methods for in vivo gene delivery, but their clinical application is often limited by immune responses, toxicity, and off-target effects. To overcome these challenges, researchers are developing engineered viral vectors with reduced immunogenicity and enhanced targeting to improve the safety and efficacy of gene therapies. One major advance is the modification of adeno-associated viruses (AAV) and lentiviral vectors (LV) to minimize immune recognition. AI-driven capsid engineering enables the creation of stealth viral vectors that evade neutralizing antibodies, enabling repeated dosing and prolonged therapeutic effects. In addition, genetic modification of viral proteins can reduce activation of innate and adaptive immune responses, preventing rapid clearance from the blood. Another breakthrough is the development of tissue-specific viral vectors with enhanced tropism. By engineering viral surface proteins, researchers can redirect viral vectors to specific organs, improving target cell transduction while minimizing off-target effects. For example, AAVs targeting the brain have been optimized to cross the blood-brain barrier (BBB), enabling gene therapy for neurodegenerative diseases. Similarly, tumor-homing viral vectors are being developed for cancer gene therapy to deliver therapeutic genes directly into solid tumors with greater precision. In addition, hybrid viral-nanoparticle systems are emerging that combine the efficiency of viral vectors with the biocompatibility of lipid nanoparticles (LNPs) to enhance gene delivery control and immune evasion. These engineered viral vectors pave the way for safer, more efficient, and highly targeted gene therapies, accelerating the development of next-generation precision medicine. References [1] Jiang-Hui Wang et al., Signal Transduction and Targeted Therapy 2024 (https://lnkd.in/duHNMwkf) [2] David Schaffer et al., Annu Rev Biomed Eng 2009 (doi: 10.1146/annurev.bioeng.10.061807.160514) #GeneTherapy #ViralVectors #AAV #Lentivirus #CapsidEngineering #SyntheticBiology #PrecisionMedicine #BiotechInnovation #Immunotherapy #GeneticMedicine #CSTEAMBiotech