Viral latency drives ‘memory inflation’: a unifying hypothesis linking two hallmarks of cytomegalovirus infection

Abstract

Low public awareness of cytomegalovirus (CMV) results from the only mild and transient symptoms that it causes in the healthy immunocompetent host, so that primary infection usually goes unnoticed. The virus is not cleared, however, but stays for the lifetime of the host in a non-infectious, replicatively dormant state known as 'viral latency'. Medical interest in CMV results from the fact that latent virus can reactivate to cytopathogenic, tissue-destructive infection causing life-threatening end-organ disease in immunocompromised recipients of solid organ transplantation (SOT) or hematopoietic cell transplantation (HCT). It is becoming increasingly clear that CMV latency is not a static state in which the viral genome is silenced at all its genetic loci making the latent virus immunologically invisible, but rather is a dynamic state characterized by stochastic episodes of transient viral gene desilencing. This gene expression can lead to the presentation of antigenic peptides encoded by 'antigenicity-determining transcripts expressed in latency (ADTELs)' sensed by tissue-patrolling effector-memory CD8 T cells for immune surveillance of latency [In Reddehase et al., Murine model of cytomegalovirus latency and reactivation, Current Topics in Microbiology and Immunology, vol 325. Springer, Berlin, pp 315-331, 2008]. A hallmark of the CD8 T cell response to CMV is the observation that with increasing time during latency, CD8 T cells specific for certain viral epitopes increase in numbers, a phenomenon that has gained much attention in recent years and is known under the catchphrase 'memory inflation.' Here, we provide a unifying hypothesis linking stochastic viral gene desilencing during latency to 'memory inflation.'

The (gradual) rise of memory inflation

“…In terms of mouse models, the most clear‐cut of these is the use of a replication‐defective recombinant adenovirus vector 16. At first sight, this ought not to work at all, since the features of the inflationary responses seen in MCMV seem to be closely linked to a persistent infection, with continuous generation of new peptides as the virus reactivates 5, 21. However, this model induces a set of immune responses which quite accurately reproduce many of the key features of memory inflation seen after MCMV infection.…”

“…(This is a little different from showing a role in viral control acutely or in the context of adoptive transfer during immunosuppression). One piece of evidence that the inflationary population is required to maintain latency comes from studies by the Reddehase group of a key early‐expressed epitope in IE1 (dominant in the BALB/c model) 5, 21, 66. It was previously noted that IE1 transcripts can be detected eg, in the lung, but IE3 was not found, suggesting a checkpoint restricting progression.…”

“…It is a striking phenomenon that was made quite evident by the use of MHC‐peptide tetramers to track responses in the infected animals over time 2, 3, 4. The term is now in reasonably common use5, 6 and the actual features of the responses induced which can be called “inflationary” are quite robustly reproducible between different laboratories using different virus stocks, mouse lines, and infection protocols. However, the immunologic phenomenon in the original papers was not tightly defined.…”

Recent advances in CMV tropism, latency, and diagnosis during aging

“…Although the overall absolute number of tissue-infiltrating CD8 + T cells declines, CD8 T cells specific for certain viral epitopes accumulate over time also in absolute numbers and assume the phenotype CD44 + CD62L − CD127 − KLRG1 + characteristic of terminally differentiated T cells known as shortlived effector cells (SLECs) (Holtappels et al 2000;Snyder et al 2008;Seckert et al 2012). This phenomenon has been coined with the now popular term Bmemory inflation^(MI) (Karrer et al 2003;Klenerman and Oxenius 2016).…”

“…Both TELs are expressed independently from a bidirectional gene pair flanking the MIE promoter-enhancer, and show a random expression pattern in the lungs of latent mice that follows the Poisson distribution. The Poisson distribution function allows us to calculate the frequency of transcriptional activity as one ie1 TEL-expressing cell out of 2500 latently infected cells at any moment (Seckert et al 2012). To date, the ie1 TEL of mCMV is the only known TEL that corresponds to an epitope-specific MI, although the amount of IE1 protein was below the limit of molecular detection.…”