Biology subjects

Naipauer, J.

Publications and source records attributed to Naipauer, J..

7 recordsLinked to original sources

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↗

bioRxiv2026

Archaic translation initiation factor eIF5B supports KSHV late lytic replication and viral oncogenesis by mimicking a hypoxic cellular landscape

Kaposis Sarcoma (KS) Herpesvirus (KSHV) is the etiological agent of KS, an AIDS-defining illness. Recent studies have demonstrated that even during normoxic conditions, KSHV facilitates replication by modulating hypoxia-inducible factors (HIFs), creating a hypoxia-like environment that promotes cellular transformation. KSHV lytic viral genes are favored for protein synthesis during infection by upregulating HIF2 and utilizing the hypoxic eIF4E2 translation initiation complex in oxygen-replete conditions. This translation initiation plasticity (TRIP) links viral replication strategies to angiogenic signaling and oncogenicity. However, the molecular basis of this plasticity remains poorly understood. This study reveals that viral inhibition of eukaryotic initiation factor 2 (eIF2) induces the use of another alternative initiation factor, eIF5B, which canonically mediates delivery of initiator methionine-tRNAiMet during hypoxia. We demonstrate through ribosome density fractionation that eIF2 accumulates in translationally inactive monosome fractions while eIF5B redistributes its translation activity toward polysomes during lytic replication. Progressive dependence on eIF5B during KSHV infection was illustrated by impaired late lytic gene expression, diminished virion production, and altered polysome profiles following eIF5B knockdown. Transcriptomic analyses further reveal that the mRNA landscape in KSHV-infected cells depleted of eIF5B mirrors that of uninfected hypoxic cells. Moreover, silencing of eIF5B in a natural infection model reduces both VEGF secretion and anchorage-independent growth--two hallmarks of KSHV viral oncogenicity. These results demonstrate that eIF5B functions as an essential component of alternative translation initiation machinery activated in response to eIF2 inactivation during KSHV lytic replication, emphasizing its key role in viral pathogenesis and its potential as a novel therapeutic target. IMPORTANCEKaposis Sarcoma Herpesvirus (KSHV) is a human cancer virus that causes severe malignancies in immunocompromised individuals, including the blood vessel cancer Kaposis Sarcoma and a highly aggressive body-cavity lymphoma. Although cells mount a response to infection by shutting down global protein synthesis, how viruses like KSHV continue making viral proteins when this cellular machinery is shutdown remains unclear. This study uncovers that KSHV exploits an ancient cellular factor typically used for protein production under low-oxygen conditions. We identify a previously unrecognized role for the translation factor, eIF5B, in supporting KSHV replication and select production of viral proteins during infection. Our work further demonstrates that KSHVs utilization of eIF5B contributes to a hypoxia-like environment during infection, ultimately contributing to cancer-promoting changes within the cell. These findings highlight a new strategy for tumor-virus reprogramming of host cells, opening an avenue for novel therapeutic targets to eliminate virus-associated cancers.

microbiology↗

bioRxiv2025

HIV Infection and Opioid Treatment Enable the Engraftment of Kaposi Sarcoma-like Tumors into Immunocompetent Mice

The Kaposi Sarcoma herpesvirus (KSHV) causes Kaposi sarcoma (KS), primary effusion lymphoma, a lymphoproliferative disease (KSHV-multicentric Castlemans disease), and a cytokine inflammatory syndrome (KICS). These diseases occur more frequently, though not exclusively, among people living with HIV or other types of immune dysregulation. While limited KS can regress with immune reconstitution, such as through antiretroviral therapy (ART) in people living with HIV, there are currently no curative treatments for advanced KS. Preventive or therapeutic vaccines targeting KSHV could have a significant clinical impact; however, the development and testing of such strategies have been limited by the lack of preclinical models that faithfully recapitulate KS, including the presence of infected spindle cells and a relevant immune microenvironment. HIV/AIDS is an important cofactor for KS, and globally, the majority of individuals with KS are HIV-infected. Current evidence indicates that HIV-1 may enable KS progression through immunosuppression and promote pathogenesis by inducing inflammatory cytokines and producing secreted regulatory proteins like Tat and Nef. The design and testing of new therapeutic approaches based on pathogenesis are hampered by the lack of models that replicate KSHV oncogenesis in the context of HIV/AIDS. In the present study, we demonstrate that KSHV-infected cells can form tumors in an immunocompetent mouse model, but only when these mice are pretreated with EcoHIV and morphine, both of which have immunomodulatory and pro-inflammatory effects. These tumors exhibit gene expression profiles and immune microenvironments that closely resemble those observed in human KS lesions. This novel KSHV tumor model in immunocompetent mice provides a valuable platform to test immunotherapeutic strategies for KS, including immunomodulatory agents, targeted antibody therapies, checkpoint inhibitors, and vaccines. Author SummaryKaposi sarcoma (KS) is a cancer caused by the Kaposis sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). A vaccine against this virus could prevent or cure this malignancy. However, there are no good animal models with an immune system to test new immunization approaches. The possibility of having KSHV-driven tumors develop in immunocompetent mice due to EcoHIV infection presents a unique opportunity to create an AIDS-KS mouse model suitable for testing immune-based therapies and KSHV vaccines in a scenario that replicates important aspects of AIDS-KS. These first-in-kind murine models incorporating a biologically relevant mouse HIV infection tool make our models unique and original, with the potential to provide novel mechanistic and pathobiological insights.

microbiology↗

bioRxiv2023

Single-cell RNA sequencing identifies KSHV-infected Mesenchymal stem cell subpopulations precursors of Kaposi's Sarcoma

Kaposis sarcoma (KS) may derive from Kaposis Sarcoma Herpesvirus (KSHV)-infected human Mesenchymal Stem Cells (hMSCs) migrating into an inflammatory and angiogenic site, enhancing KS initiation. KSHV infection of primary hMSCs uncovers specific cell subpopulations, mechanisms, and conditions involved in the first steps of the KSHV-induced transformation and reprogramming process toward KS progenitor cells. The pro-angiogenic environmental conditions allowed KSHV to reprogram hMSCs closer to KS gene expression profiles and points to KSHV infection as an important factor inducing the Mesenchymal-to-Endothelial (MEndT) transition of hMSC. Single-cell RNA-sequencing analysis revealed a subpopulation of infected cells growing in a pro-angiogenic environment with both viral and host oncogenes upregulation. This highlights the importance of this condition in boosting the KSHV-induced transformation and reprogramming of hMSC towards MEndT and closer to KS gene expression profiles, reinforcing the notion of these cell subpopulations as KS precursors.

microbiology↗

bioRxiv2021

A non-coding RNA network involved in KSHV tumorigenesis

Regulatory pathways involving non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA) have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat, Neat1, H19, Meg3 and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and Cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.

cancer biology↗

bioRxiv2019

PDGFRA Defines the Mesenchymal Stem Cell Kaposi’s Sarcoma Progenitors by Enabling KSHV Oncogenesis in an Angiogenic Environment

Kaposis sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (P(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected P(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected P(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.\n\nAUTHOR SUMMARYIdentification of the KS progenitor cell creates the possibility of studying viral oncogenesis and its determinants from its initial steps as a continuum. It also increases our understanding of pathogenic mechanisms and disease preferential tropism. Hereby we identify P(+)S-MSCs as KS progenitors, in which KSHV infection has oncogenic consequences; only when these cells are in a pro-angiogenic environment in which PDGFRA activation enables an oncogenic de-repressed KSHV epigenome. These results identify a KS-progenitor population in the P(+)S-MSCs and point to pro-angiogenic environmental conditions as essential for oncogenic viral gene expression and transformation. We designed a novel model of KSHV oncogenesis, creating a very robust platform to identify KSHV oncogenic pathways and their relationship with cellular lineages and extracellular growth environments.

cancer biology↗

bioRxiv2019

A major Role for Nrf2 transcription factors in cell transformation by KSHV encoded oncogenes.

Kaposi s sarcoma (KS) is the most common tumor in AIDS patients and the highly vascularized patient s skin lesions are composed of the cells that derive from the endothelial tissue transformed by the KSHV virus. Heme oxygenase-1 (HO-1) is an enzyme upregulated by the Kaposi s sarcoma-associated herpesvirus (KSHV) and highly expressed in human Kaposi Sarcoma (KS) lesions. The oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR) is expressed by the viral genome in infected cells and is involved in KS development, HO-1 expression and vascular endothelial growth factor (VEGF) expression. We have characterized that vGPCR induces HO-1 expression and HO-1 dependent transformation through the Ga13 subunit of heterotrimeric G proteins and the small GTPase RhoA. We have found here several lines of evidence that support a role for Nrf2 transcription factors and family members in the vGPCR,-Ga13,-RhoA signaling pathway that converges on the HO-1 gene promoter. Our current information assigns a major role to Erk1/2 MAPK pathways as intermediate in signaling from vGPCR to Nrf2, influencing Nrf2 translocation to the cell nucleus, Nrf2 transactivation activity and consequently HO-1 expression. Experiments in nude mice show that the tumorigenic effect of vGPCR is dependent on Nrf2 suggesting this transcription factor or its associated proteins as putative pharmacological or therapeutic targets in KS.

cancer biology↗