Montani, M. | Search bioRxiv

bioRxiv2026

Kaposi Sarcoma Herpes Virus Reprograms Mesenchymal Cell Glycosylation to control platelet-derived growth factor receptor A signaling

Kaposi sarcoma-associated herpesvirus (KSHV) reprograms host cellular pathways to promote viral persistence and tumor development by supporting the survival and expansion of infected and bystander cells. Among the signaling axes implicated in this process, oncogenic activation of receptor tyrosine kinases, particularly platelet-derived growth factor receptor alpha (PDGFRA), is a well-established hallmark of Kaposi sarcoma pathogenesis. However, the impact of virus-driven cell surface glycosylation changes in PDGFRA-associated signaling remains uncertain. Here, we identified a critical role for KSHV in reshaping the glycosylation landscape of mesenchymal stromal cells (MSCs), thereby reprogramming PDGFRA signaling. We show that KSHV infection enhances a unique glycan profile in human and mouse MSCs, enriched in branched complex N-glycans with limited (2-6) sialylation, Transcriptomic analyses of KSHV-infected MSCs and Kaposis Sarcoma patient samples revealed a coordinated dysregulation of pathways involved in carbohydrate metabolism, nucleotide-sugar transport, and sialic acid turnover, with a particular focus on sialic acid turnover (NPL/NEU3), the UDP-N-acetylglucosamine transporters SLC35A3/B4, and complex N-glycan elongation (MGAT5/B3GNT2/B4GALT1) as critical nodes underlying reduced (2-6) sialylation and increased N-glycan branching. This remodeled glycan landscape contributes to create a permissive context for galectin-1 (Gal-1) binding, which in turn enhances PDGFRA activation and downstream signaling. These findings identify an integral component of KSHV-driven mesenchymal cell reprogramming, unveiling a lectin-dependent mechanism of RTK activation in Kaposi sarcoma pathogenesis.

Cancer Biology↗

bioRxiv2023

Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and, in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. To precisely engineer bnAb boosting immunogens, we used molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identified Env mutations that were predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encoded antibody affinity gains and selected for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

immunology↗