Abstract
Epstein Barr virus (EBV) persists as a latent herpes virus infection in the majority of the adult human population. The virus can reactivate from this latent infection into lytic replication for virus particle production. Here, we report that autophagic membranes, which engulf cytoplasmic constituents during macroautophagy and transport them to lysosomal degradation, are stabilized by lytic EBV replication in infected epithelial and B cells. Inhibition of autophagic membrane formation compromises infectious particle production and leads to the accumulation of viral DNA in the cytosol. Vice versa, pharmacological stimulation of autophagic membrane formation enhances infectious virus production. Atg8/LC3, an essential macroautophagy protein and substrate anchor on autophagic membranes, was found in virus preparations, suggesting that EBV recruits Atg8/LC3 coupled membranes to its envelope in the cytosol. Our data indicate that EBV subverts macroautophagy and uses autophagic membranes for efficient envelope acquisition during lytic infection.
Highlights
Epstein Barr virus (EBV), a γ-herpes virus, is a remarkably successful human pathogen with more than 95% of the entire adult human population being infected (Rickinson et al, 2014). 50 years ago, EBV was discovered as the first human tumor virus candidate in tissue samples of Burkitt's lymphoma patients (Epstein et al, 1964)
These cells did not display any expression of the BamH1 Z fragment leftward reading frame 1 (BZLF1) protein upon cross-linking, verifying that these cells are EBV negative and do not enter lytic EBV replication, which is initiated by BZLF1 (Fig. 1C)
Our study demonstrates the incorporation of membranes that have been modified by the macroautophagy machinery into virus particles
Summary
Epstein Barr virus (EBV), a γ-herpes virus, is a remarkably successful human pathogen with more than 95% of the entire adult human population being infected (Rickinson et al, 2014). 50 years ago, EBV was discovered as the first human tumor virus candidate in tissue samples of Burkitt's lymphoma patients (Epstein et al, 1964). Cell-mediated immune control is thought to keep persistent EBV infection in check and prevent virus-associated malignancies. These malignancies harbor latent EBV proteins, which drive cellular proliferation and survival in order for EBV infected B cells to gain access to the memory B cell pool, Abbreviations: EBV, Epstein Barr virus; Atg, autophagy related gene; BMRF1, BamH1 M fragment rightward reading frame 1; BZLF1, BamH1 Z fragment leftward reading frame 1; BHRF1, BamH1 H fragment rightward reading frame 1; BALF1, BamH1 A fragment leftward reading frame 1; BALF4, BamH1 A fragment leftward reading frame 4; BRLF1, BamH1 R fragment leftward reading frame 1; BNRF1, BamH1 N fragment rightward reading frame 1; EBNA1, Epstein Barr virus nuclear antigen 1; LMP1, latent membrane protein 1; vFLIP, viral FLICE-like inhibitor protein. No requirement of macroautophagy for the replication of these α- and βherpes viruses was reported so far
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