Antiviral therapy can reverse the development of immune senescence in elderly mice with latent cytomegalovirus infection

Cytomegalovirus (CMV) infection leads to the development of adaptive and humoral immune responses that are amongst the largest for any pathogen and intriguingly the magnitude of the immune response increases with age, a phenomenon termed 'memory inflation'. Elevated CMV-specific immunity has been correlated with an increased mortality rate of elderly individuals and impaired vaccination responses. The latent phase of CMV infection is characterised by intermittent episodes of subclinical viral reactivation and the production of immunogenic transcripts that may maintain memory inflation of virus-specific cytotoxic lymphocytes. However, the relative importance of CMV reactivation in the development of memory inflation is uncertain as is the potential for anti-viral treatment to reverse this effect. Here we administered valaciclovir for up to 12 months in mice with established murine CMV (MCMV) infection. Treatment reduced the magnitude of the MCMV-specific CD8(+) T-lymphocyte response by 80% and the residual MCMV-tetramer specific lymphocytes exhibited a less differentiated phenotype. In addition, latent MCMV infection suppressed the proportion of naïve CD8(+) T-cells by 60% compared to the treated mice or MCMV negative animals. Furthermore, anti-herpes viral treatment lead to a reduction in influenza A viral loads following challenge in elderly MCMV-infected animals and reduced the differentiation of influenza virus-specific cytotoxic lymphocytes. These observations demonstrate that MCMV-specific memory inflation is maintained by viral replication and therapeutic intervention could lead to improved immune function.