An attenuated temperature‐sensitive strain of cytomegalovirus (tsm5) establishes immunity without development of CD8⁺ T cell memory inflation

Abstract

Cytomegalovirus (CMV) is a widely prevalent herpesvirus that is well tolerated by an immune competent host yet establishes a state of chronic infection. The virus is thought to undergo frequent subclinical episodes of reactivation which leads to an unusually large accumulation of CMV-specific CD8(+) T lymphocytes in the peripheral blood, a phenomenon termed "memory inflation." The high magnitude of the CMV T cell response has been implicated in impaired immunity to heterologous pathogens such as EBV, influenza and West Nile virus. Here, using murine CMV (MCMV), we show that memory inflation of virus-specific CD8(+) T cells is avoided if mice are infected with a replication defective virus called temperature-sensitive mutant 5 (tsm5), which carries an attenuating mutation within the DNA primase gene. Mice infected with tsm5 do generate primary T cell responses towards viral proteins but these do not amass to skew the memory repertoire of CD8(+) T cells. Therefore, attenuation of the virus replication machinery may be valuable in future CMV vaccine designs because the virus remains immunogenic but does not contribute to CMV associated T cell immune senescence.

Cytomegalovirus infection and progressive differentiation of effector-memory T cells

“…Most of these concentrated on eliciting antibodies but some (also) aimed to induce robust CMV-specific T-cell immunity 59 – 61 . Vaccination with live-attenuated and replication-deficient CMV vectors seems to induce CD8 + T-cell responses undergoing less memory inflation, including the induction of the associated EM cell phenotype 62 , 63 . Vaccination with synthetic long peptides containing MCMV epitopes induces strong and polyfunctional CD8 + T-cell responses, but whereas responses to these epitopes are inflationary in the MCMV setting, they are non-inflationary in the peptide vaccine setting, which corresponds with their reduced EM-like phenotype 64 , 65 .…”

Novel viral vectors in infectious diseases

“…However, HCMV is pathogenic, and attenuated vectors are necessary for translation into humans. In mice, temperature‐sensitive mCMV fails to induce robust virus‐specific CD8 + T‐cell memory, eliminating this strategy from exploration for vector attenuation. Encouragingly, however, spread‐deficient mCMV vectors lacking the surface glycoprotein L or the virion protein M94 induce robust T‐cell immunity.…”

Optimal CD8+ T‐cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

“…Thus, the development of ‘safe’ non‐replicating CMV vectors was first explored using the murine CMV (MCMV) model. Whereas temperature‐sensitive MCMV failed to induce robust virus‐specific CD8 + T‐cell memory [ 14 ], OVA‐expressing virus lacking the gene M94 (MCMV‐ΔM94), which is essential for secondary envelopment and cell‐to‐cell spread of MCMV [ 15 ], induced OVA‐specific CD4 + and CD8 + T‐cell responses following systemic challenge [ 16 ]. Furthermore, ΔgL‐MCMV lacking the essential viral glycoprotein L (gL) required for viral cell spread induced MCMV‐specific CD8 + T‐cell memory inflation when administered systemically (intraperitoneally), albeit generally to a lesser degree than replicating virus.…”