Biology Reference
In-Depth Information
Unexpectedly, the genome copy numbers of the triple-deleted virus were com-
parable to WT MCMV during the acute phase of infection, although this could
be explained by NK cell control early in infection prior to the robust CD8
+
T cell
response (Gold et al. 2004). Even more surprising was the ability of the triple
knockout to establish infection for at least 6 weeks, after which it was able to
reactivate upon immunosuppression the mice (Gold et al. 2004). Perhaps the
redundancy of immune evasion mechanisms, most notably the modulation of T
cell and NK cell activating signals (see Sects. 2.3 and 3 below), enables this dele-
tion virus to survive. It is also possible that VIPRs facilitate transmission since
salivary gland titers of the triple-deleted virus were lower than WT virus (Lu
et al. 2006). It is further conceivable that VIPRs are required for superinfection
of CMV-immune individuals (Booth et al. 1993; Boppana et al. 2001; Rizvanov
et al. 2003). Finally, the use of inbred laboratory mice might not accurately
reflect the infection and spread of CMV in an outbred population. Thus, addi-
tional studies of animal CMVs in outbred populations might help to establish the
role of VIPRs in vivo.
CMV Interference with T Cell Costimulation
HCMV UL144
UL144 encodes the only known tumor necrosis factor receptor superfamily mem-
ber (TNFRSF) among herpesviruses (Locksley et al. 2001; Croft 2003; Ware
2003) (TNFR-homologs are widespread in poxviruses). UL144 shows strong
sequence similarity to the herpes simplex virus entry mediator (HVEM) (Benedict
et al. 1999). Recently, both HVEM and UL144 have been shown to interact with
B and T lymphocyte attenuator (BTLA), a member of the Ig superfamily that
negatively regulates T cell proliferation (Cheung et al. 2005). The interaction
with BTLA suggests that UL144 mimics the inhibitory co-signaling function of
HVEM. UL144 was further shown to induce NFκB-dependent transcription by
sequestering TRAF6 (Poole et al. 2006). The UL144 gene shows significant
strain-specific variability of up to 21% difference in the nucleotide as well as the
amino acid sequence (Lurain et al. 1999; Arav-Boger et al. 2002). The polymor-
phism of UL144 was investigated in the context of congenital CMV disease.
Although some groups reported a significant association between the UL144
subtype and the outcome of the CMV infection (Arav-Boger et al. 2002, 2006;
He et al. 2004; Tanaka et al. 2005), there are other reports claiming the opposite
(Bale et al. 2001; Murayama et al. 2005; Picone et al. 2005; Mao et al. 2007).
Interestingly, a natural variant of RhCMV, strain 180.92, was recently reported
to lack UL144, which is present in strain 68.1 (Hansen et al. 2003; Rivailler et al.
2006). Natural UL144 variants as well as UL144 deletion might enable in vivo
studies to address the role of UL144 in immune evasion and CMV disease.
