Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus

PLoS Pathogens, Dec 2012

In addition to its surface glycoprotein (GP1,2), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP1,2 and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP12 antibodies, but only from mice that have been immunized by sGP. We term this phenomenon “antigenic subversion”, and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP1,2, thereby allowing it to absorb anti-GP1,2 antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP1,2 response resulting in strong cross-reactivity with sGP. This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design.

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Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus

Yang C (2012) Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus. PLoS Pathog 8(12): e1003065. doi:10.1371/journal.ppat.1003065 Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus Gopi S. Mohan 0 Wenfang Li 0 Ling Ye 0 Richard W. Compans 0 Chinglai Yang 0 Christopher F. Basler, Mount Sinai School of Medicine, United States of America 0 1 Department of Microbiology and Immunology, Emory University , Atlanta , Georgia , United States of America, 2 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou , People's Republic of China In addition to its surface glycoprotein (GP1,2), Ebola virus (EBOV) directs the production of large quantities of a truncated glycoprotein isoform (sGP) that is secreted into the extracellular space. The generation of secreted antigens has been studied in several viruses and suggested as a mechanism of host immune evasion through absorption of antibodies and interference with antibody-mediated clearance. However such a role has not been conclusively determined for the Ebola virus sGP. In this study, we immunized mice with DNA constructs expressing GP1,2 and/or sGP, and demonstrate that sGP can efficiently compete for anti-GP12 antibodies, but only from mice that have been immunized by sGP. We term this phenomenon ''antigenic subversion'', and propose a model whereby sGP redirects the host antibody response to focus on epitopes which it shares with membrane-bound GP1,2, thereby allowing it to absorb anti-GP1,2 antibodies. Unexpectedly, we found that sGP can also subvert a previously immunized host's anti-GP1,2 response resulting in strong cross-reactivity with sGP. This finding is particularly relevant to EBOV vaccinology since it underscores the importance of eliciting robust immunity that is sufficient to rapidly clear an infection before antigenic subversion can occur. Antigenic subversion represents a novel virus escape strategy that likely helps EBOV evade host immunity, and may represent an important obstacle to EBOV vaccine design. - Funding: This study is supported by Public Health Service grants 1R01AI093406 and 1R01AI069148 from the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Ebola virus (EBOV) is an enveloped single-stranded negative-sense RNA virus in the order Mononegavirales, which along with the Marburg virus (MARV) forms the Filovirus family. EBOV is the etiologic agent of Ebola Hemorrhagic Fever (EHF), a highly lethal hemorrhagic fever with up to 90% mortality [1]. Since its discovery in 1976, EBOV has caused sporadic outbreaks in Sub-Saharan Africa with death tolls in the hundreds. Interestingly, while filoviruses have been only recently discovered, they are one of the few non-retrovirus RNA paleoviruses identified in mammalian genomes, suggesting an ancient relationship with mammals [2,3]. Growing evidence suggests that bats are the natural reservoir of EBOV in the wild today [46]. Current treatment for Ebola hemorrhagic fever is purely supportive, and the lack of effective interventions underscores the importance of developing a broadly-protective vaccine that confers long-lasting immunity. The ability to develop such a vaccine is critically dependent on our understanding of the mechanisms by which EBOV suppresses, distracts, or otherwise evades the host immune response [7]. One widely hypothesized immune evasion mechanism employed by Ebola virus is secretion of a truncated viral glycoprotein by EBOV infected cells. The EBOV surface glycoprotein (GP1,2) mediates host cell attachment and fusion, and is the primary structural component exposed on the virus surface. For this reason, GP1,2 is the focus of most EBOV vaccine research, and it is generally accepted that a robust anti-GP1,2 antibody response is crucial for protection against lethal EBOV challenge [8]. EBOV GP1,2 forms trimeric spikes on virion surfaces similarly to influenza HA and HIV Env [9]. Also like HA and Env, GP is first synthesized as an uncleaved precursor (GP0) which is then cleaved in the Golgi complex by the protease furin [10] into two functional subunits: The N-terminal GP1 subunit contains the putative receptor-binding domain (RBD), and the Cterminal GP2 subunit contains the fusion apparatus and transmembrane domain. GP1,2 is encoded in two disjointed reading frames in the virus genome. The two reading frames are joined together by slippage of the viral polymerase at an editing site (a tract of 7-As) to insert an 8th A, generating an mRNA transcript that allows read-through translation of GP1,2 [11,12]. However, only about 20% of transcripts are edited, while the remaining 80% of unedited transcripts have a premature stop codon, resulting in synthesis of a truncated glycoprotein product (sGP) which is s (...truncated)


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Gopi S. Mohan, Wenfang Li, Ling Ye, Richard W. Compans, Chinglai Yang. Antigenic Subversion: A Novel Mechanism of Host Immune Evasion by Ebola Virus, PLoS Pathogens, 2012, Volume 8, Issue 12, DOI: 10.1371/journal.ppat.1003065