Characterization of 90K/LGALS3BP as antiviral factor
Auch gedruckt in der BibliothekW: W-H 14.086
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2015-02-27
Cellular restriction factors inhibit HIV-1 at different stages of its replication cycle. One hallmark of these antiviral proteins is their interferon-inducible expression. The secreted glycoprotein 90K is also upregulated by interferon and induced in HIV-1 infected people. Herein, 90K was characterized as novel antiviral factor against HIV-1. Cellular 90K reduced the particle infectivity of HIV-1 progeny. Flow cytometry analysis revealed reduced levels of gp120 at the cell surface in presence of 90K expression leading to a lack in viral envelope incorporation. Additionally, a 90K induced processing defect of the gp160 precursor to mature gp120 and gp41 was observed, but seems to be uncoupled from the envelope incorporation defect. 90K did not act as a general inhibitor of furin cleavage nor did it trap Envelope in the endoplasmic reticulum. Envelope and 90K are both trafficked through the secretory pathway and therefore highly co-localize within cellular compartments, but direct interaction was not observed by co-immunoprecipitation. The antiviral activity of 90K was mapped to the two central protein binding domains BTB/POZ and IVR. 90K´s antiviral potential was conserved between 90K orthologs from six non-human primates. In contrast, 90K derived from rhesus macaques and the mouse homolog CypCAP failed to inhibit HIV-1, indicating 90K´s species specificity. Importantly, 90K is expressed in HIV-1 relevant CD4+ T cells, PBMCs and primary macrophages. In the latter, 90K expression is further stimulated by type I interferons. siRNA mediated knockdown of 90K in primary macrophage and PBMC cultures led to improved virus production. Silencing of 90K expression in primary macrophages boosted particle infectivity and enhanced Envelope incorporation into HIV-1 progeny virions. 90K also inhibited HIV-2 and SIVmac239, pointing toward a broader antiviral spectrum. Conclusively, 90K constitutes a relevant novel antiviral factor against HIV-1.
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Viral envelope proteins