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Transcripts expressed in cytomegalovirus latency coding for an antigenic IE/E phase peptide that drives “memory inflation”

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Abstract

Roizman’s definition of herpesviral latency, which applies also to cytomegaloviruses (CMVs), demands maintenance of reactivation-competent viral genomes after clearance of productive infection. It is more recent understanding that failure to complete the productive viral cycle for virus assembly and release does not imply viral gene silencing at all genetic loci and all the time. It rather appears that CMV latency is transcriptionally “noisy” in that silenced viral genes get desilenced from time to time in a stochastic manner, leading to “transcripts expressed in latency” (TELs). If a TEL happens to code for a protein that contains a CD8 T cell epitope, protein processing can lead to the presentation of the antigenic peptide and restimulation of cognate CD8 T cells during latency. This mechanism is discussed as a potential driver of epitope-selective accumulation of CD8 T cells over time, a phenomenon linked to CMV latency and known as “memory inflation” (MI). So far, expression of an epitope-encoding TEL was shown only for the major immediate-early (MIE) gene m123/ie1 of murine cytomegalovirus (mCMV), which codes for the prototypic MI-driving antigenic peptide YPHFMPTNL that is presented by the MHC class-I molecule Ld. The only known second MI-driving antigenic peptide of mCMV in the murine MHC haplotype H-2d is AGPPRYSRI presented by the MHC-I molecule Dd. This peptide is very special in that it is encoded by the early (E) phase gene m164 and by an overlapping immediate-early (IE) transcript governed by a promoter upstream of m164. If MI is driven by presentation of TEL-derived antigenic peptides, as the hypothesis says, one should find corresponding TELs. We show here that E-phase and IE-phase transcripts that code for the MI-driving antigenic peptide AGPPRYSRI are independently and stochastically expressed in latently infected lungs.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB490, individual project E4 “Antigen presentation under the influence of murine cytomegalovirus immune evasion genes” (M.G., B.K, and C.K.S.), and SFB1292, individual project TP11 “Viral evasion of innate and adaptive immune cells and inbetweeners” (A.R, J.K.S., and N.A.W.L.).

Author information

Correspondence to Niels A. W. Lemmermann.

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The authors declare that they have no conflict of interest.

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Animal experiments were approved according to German federal law §8 Abs. 1 TierSchG by the ethics committee of the Landesuntersuchungsamt Rheinland-Pfalz, permission number 177-07/G 10-1-052.

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This article is part of the Special Issue on Immunological Imprinting during Chronic Viral Infection.

Edited by: Stipan Jonjic.

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Renzaho, A., Schmiedeke, J.K., Griessl, M. et al. Transcripts expressed in cytomegalovirus latency coding for an antigenic IE/E phase peptide that drives “memory inflation”. Med Microbiol Immunol 208, 439–446 (2019). https://doi.org/10.1007/s00430-019-00615-8

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Keywords

  • Antigen presentation
  • Antigenic peptide(s)
  • CD8 T cells
  • Gene m164
  • IE1 peptide
  • Latency
  • Latent infection
  • Memory inflation (MI)
  • RT-qPCR
  • Stochastic gene expression
  • Transcripts expressed in latency (TEL)
  • Viral gene expression