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Immunization of mice with virus-like vesicles of Kaposi sarcoma-associated herpesvirus reveals a role of ORF4 in complement-mediated neutralization

ABSTRACT: The development of a prophylactic vaccine for Kaposi sarcoma-associated Herpesvirus (KSHV) would prevent consequences from infection including disorders such as Kaposi sarcoma and primary effusion lymphoma. Here, we study the immunogenicity of noninfectious virus-like vesicles (VLVs) of KSHV as a potential future vaccine platform. VLVs present a repertoire of viral structural proteins but are noninfectious due to a defect in capsid formation that prevents viral DNA packaging. Immunization of mice with adjuvanted VLVs results in virus-specific antibodies and T cells. These antibodies neutralize viral infection, and this neutralization is enhanced by the complement system. Complement-enhanced neutralization is dependent on antibodies targeting the SCR region of viral ORF4. However, this activity was not present in serum from KSHV-infected humans. Our study highlights an important role of antibody effector functions in the development of a future KSHV vaccine

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human) Human Gammaherpesvirus 8

TISSUE(S): Epithelial Cell

SUBMITTER: Jeffrey Johnson

LAB HEAD: Jeffrey Johnson

PROVIDER: PXD035478 | Pride | 2023-02-01

REPOSITORIES: Pride

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CD109 is novel KSHV entry receptor in human endothelial cells and enhances infection during cellular senescence

Project description:The aging process is characterized by cellular functional decline and increased susceptibility to infections. Understanding the association between virus infection and aging is crucial for developing effective strategies against viral infections in older individuals. Kaposi's sarcoma-associated herpesvirus (KSHV) infection increases the risk of Kaposi's sarcoma, a vascular cancer prevalent among the elderly without HIV infection. However, the relationship between KSHV pathogenesis and cellular senescence remains unknown. Here, we demonstrate that KSHV infectivity is significantly increased in senescent human endothelial cells due to enhanced binding of virions to cell surface. Proteomic analysis identified caveolin-1 and CD109 that promote KSHV infection and were significantly upregulated in senescent cells. In particular, CD109 is expressed on cell surface and directly interacts with KSHV virions to enhance KSHV infection. Knockout of CD109 abolished while overexpression of CD109 promote KSHV binding to cell surface, and infectivity. These results identify CD109 as a novel KSHV entry receptor that enhances KSHV infection in senescent cells, which might in part explain the higher sensitivity of elder subjects to KSHV infection and Kaposi's sarcoma.

2024-04-17 | PXD048212 | Pride

Hijacking of Nucleotide Biosynthesis and Deamidation-mediated Glycolysis by an Oncogenic Herpesvirus

Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS) and multiple types of B cellmalignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributesto viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorlyunderstood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the denovo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cellproliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediatedpyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion orpharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primaryeffusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanismunderpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and otherdiseases.

2024-02-16 | PXD043435 | Pride

Quantitative proteomics analysis of lytic KSHV infection in human endothelial cells reveals novel targets of viral immune modulation

Project description:Kaposi’s Sarcoma associated herpesvirus (KSHV) is an oncogenic human virus and leading cause of mortality in HIV infection. Reactivation of KSHV from latent to lytic stage infection initiates a cascade of viral gene expression, and here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following lytic KSHV reactivation, we quantify >7000 cellular and 71 viral proteins. Lytic KSHV infection resulted in >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. A complementary KSHV genome-wide CRISPR genetic screen identified K5 as the viral gene responsible for the downregulation of two novel KSHV targets, Nectin-2 and CD155, both ligands of the NK cell DNAM-1 receptor. Despite the high episome copy number, we show that CRISPR Cas9 provides a remarkably efficient way to target KSHV genomes.

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Quantitative proteomics analysis of lytic KSHV infection in human endothelial cells reveals novel targets of viral immune modulation

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HIF1α enrichment on KSHV genome in normoxia and hypoxia

Project description:Chromatin Immuno-precipitaion sequencing was performed using HIF1 alpha antibodies to investigate its enrichment on Kaposi's sarcoma associated herpesvirus (KSHV) genome in BC3 cells and purified KSHV infected PBMCs under normoxic or hypoxic conditions

2020-11-01 | GSE149401 | GEO

Anti-SARS-CoV-2 antibodies elicited by COVID-19mRNA vaccine exhibits a unique glycosylation pattern

Project description:Messenger RNA-based vaccines against COVID-19 induce a robust anti-SARS-CoV-2 antibody response with potent viral neutralization activity. Antibody effector functions is determined by its constant region subclasses as well as by its glycosylation patterns, but their role in vaccine efficacy is not well understood. Moreover, whether vaccination induce antibodies with similar Fc structures and protection potential as in COVID-19 patients remains unclear. Here, we analyzed BNT162b2 vaccine-induced IgG subclass distribution and Fc glycosylation patterns, as well as their potential to drive effector function via Fc-gamma receptors and complement pathways. We identified a unique Fc composition of these antiviral protein antibodies that is distinct from COVID-19 patients and convalescences. Vaccine-induced anti-spike SARS-CoV-2 IgG displayed a pro-inflammatory Fc profile and superior Fab- and Fc-mediated function, as compared to antibodies generated during natural viral infection. Moreover, differences in the kinetics of IgG Fc structure formation and their engagement with immune receptors were observed between different age groups. These data highlight the heterogeneity of the IgG Fc response to SARS-CoV-2 infection and vaccination and suggest that they differently support long-lasting protection.

2021-11-29 | PXD029321 | Pride

microRNA Targetome Analysis of Latently KSHV-infected Primary Effusion Lymphoma Cell lines Using PAR-CLIP [Illumina]

Project description:Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and, often, EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in viral latency and lymphomagenesis. Here we report the direct and transcriptome-wide identification of miRNA target sites for all miRNAs expressed in PEL cell lines. The resulting dataset revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs encoding proteins that function in pathways with relevance to KSHV pathogenesis. Moreover, ~50% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, these experiments identify an extensive list of mRNAs targeted by KSHV miRNAs and indicate that these are likely to strongly influence viral replication and pathogenesis. small RNA sequencing, 3 samples Ago2 (EIF2C2) PAR-CLIP, 2 samples

2011-11-16 | E-GEOD-32109 | biostudies-arrayexpress

KSHV uses viral IL6 to expand infected immunosuppressive macrophages (scRNA-seq)

Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi’s sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases infected cell populations is crucial for curing KSHV-associated diseases. Here, we demonstrate that KSHV preferentially infects CD14+ monocytes and sustains viral replication through the viral interleukin-6 (vIL-6)-mediated activation of STAT1 and 3. Using vIL6-sufficient and vIL6-deficient recombinant KSHV, we demonstrated that vIL6 plays a critical role in promoting the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL6-sufficient (wild type) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL6-deficient KSHV infection or uninfected control. These results highlight a clever strategy, in which KSHV utilizes vIL6 to secure its initial viral pool by expanding infected dysfunctional macrophages. This mechanism also facilitates KSHV to escape from host immune surveillance and to establish a lifelong infection.

2023-08-30 | GSE227166 | GEO

KSHV uses viral IL6 to expand infected immunosuppressive macrophages (RNA-seq)

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TREx-BCBL1-RTA GPRC5A-FLAG Immunoprecipitation LC-MS

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2023-07-20 | PXD039669 | Pride

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