CMV Infection as Immunomodulator in an MS Model Figure 1. MCMV infection preserves motor function in SJL/J mice undergoing TMEV induced demyelinating syndrome. SJL/J mice infected with MCMV two weeks prior to TMEV infection have significantly higher rotarod scores compared to controls that received PBS injection instead of MCMV The intergroup difference first reaches significance at 3 months, and remains significant beyond that time point (p#0.024). The figure also shows data acquired in mice infected with MCMV two weeks after TMEV infection; the data in those mice is virtually identical to our PBS/ TMEV control group. Error bars represent SD. doi:10.1371/journal.pone.0032767.g001 initiating role for EBV was suggested as far back as 1983 in a study where the HCMV infection rate and HCMV complement fixing antibody production was found to be lower in MS cases [16]. However, a study on post-mortem brain tissue using PCR based detection techniques failed to find any statistically significant association between MS and common viral infections including HCMV and EBV [17]. Meanwhile, a study in Norway found elevated titers to EBV but not to HCMV in MS cases [18]. Recently, Ascherio reported a pathogenic role of EBV in MS whereas no similar association was found regarding HCMV [5]. More recently, EBV-specific CD8+ T-cell responses were shown to be decreased in patients with clinically isolated syndrome (CIS). In contrast, there was no difference between categories for EBV- specific CD4+ T cell, or for HCMV-specific CD4+ and CD8+ T- cell responses [19]. Intrathecal enrichment in EBV-, but not HCMV-specific CD8+ CTL was also reported in early MS patients by another group [20]. EBV but not HCMV IgG antibody indexes were also increased in the CSF in this study. These studies overwhelmingly demonstrate that while EBV may be an important ‘‘trigger’’ of MS development, HCMV doesn’t contribute to MS pathogenesis. A surprising finding about HCMV was its potential protective role in MS, both from the standpoint of MRI and functional outcome measures, suggesting that HCMV infection in MS patients results in a beneficial modulation of the immune response [8]. This previous study demonstrated that recent HCMV infection either by 1) primary infection or 2) secondary infection (since humans can be infected with multiple CMV strains), or 3) reactivation of latent virus leading to recent replication has occurred in those patients, as reflected by the increased HCMV antibody titers. Therefore, it is possible CMV-specific T cells were activated or cytokine induction occurred, which has had an immunomodulatory effect resulting in attenuated MS phenotype. It is clear that both HCMV and MCMV infection affect the responsiveness of T cells since CMV infected dendritic cells can modulate naive and antigen specific T cell responses [21]. There is also evidence that HCMV may cause activation of immunomod- ulating and immune evasion mechanisms [22,23] which could alter the adaptive immune processes involved in the pathogenesis of MS [24]. The role of HCMV as an immunomodulating virus has been recognized in solid organ transplantation where it appears to contribute to the immunosuppressed state [25]. PLoS ONE | www.plosone.org 3 February 2012 | Volume 7 | Issue 2 | e32767