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not induce full activation of the IFN pathway (Browne et al. 2001; Simmen et al.
2001). These observations suggest that HCMV limits the induction of IFNβ and
ISG transcription and perhaps even JAK/STAT signaling through the actions of
viral products synthesized during infection or introduced with the virus particle.
Unlike HCMV, in vitro infection with rhesus CMV (RhCMV) fails to induce innate
antiviral gene transcription or activate IRF3 or NFκB (DeFilippis and Früh 2005).
In addition, RhCMV infection prevents IRF3 activation by UV-inactivated HCMV
particles (DeFilippis and Früh 2005). Interestingly, lack of ISG-induction is also
observed when RhCMV particles were UV-inactivated or in the presence of
cycloheximide, indicating that perhaps a component of the RhCMV virion is
responsible for this interference.
Much attention has focused on components of the CMV virion tegument, a pro-
teinaceous region composed of virus-encoded proteins located between the nucleo-
capsid and the envelope (Varnum et al. 2004). A major tegument constituent that
has been shown to possess immunomodulatory capability is phosphoprotein pp65
(Odeberg et al. 2003; Arnon et al. 2005). Infection with a pp65-deleted HCMV
(RVAd65) induces higher levels of IFNβ and ISGs than infection with wild type
(WT) HCMV (Browne and Shenk 2003; Abate et al. 2004). However, the molecu-
lar basis for this increase remains controversial. Browne et al. showed increased
nuclear translocation and DNA binding by NFκB and increased DNA binding by
IRF1 following infection with RVAd65, whereas IRF3 activation was similar to
WT. Abate et al. did not observe IRF3 activation by WT HCMV (contrary to
numerous other reports), but infection with RVAd65 induced IRF3 nuclear accu-
mulation, whereas NFκB was similarly activated by both viruses.
Recent work (Taylor and Bresnahan 2005, 2006a, 2006b) showed that the
HCMV immediate early 86 kDa protein (IE2-86) inhibits transcription of IFNβ
and RANTES by interfering with NFκB activation (Fig. 1) (Taylor and Bresnahan
2006a). The same group showed that deletion of the pp65 ORF (UL83) interferes
with expression of the adjacent protein pp71 (ORF UL82), which is transcribed
as a bicistronic mRNA with pp65 (UL83) (Ruger et al. 1987; Taylor and
Bresnahan 2006b). Since pp71 is a positive regulator of IE promoters (Bresnahan
and Shenk 2000; Cantrell and Bresnahan 2005), the increased ISG induction by
RVAd65 is likely the result of reduced IE2-86 expression. In contrast, inserting
stop codons into the pp65 ORF does not affect pp71 expression and the resulting
virus does not differ from WT with respect to expression of IFNβ and RANTES
(Taylor and Bresnahan 2006b).
CMV Interference with JAK/STAT Signal Transduction
HCMV has been shown to block IFNα-stimulated gene expression (Miller et al.
1999; Paulus et al. 2006) following viral gene expression and an initial ISG acti-
vation phase (Paulus et al. 2006). A recent study uncovered an association
between HCMV IE 72 kDa protein and STAT2 that prevented DNA binding by
