Biology Reference
In-Depth Information
The Rat Cytomegalovirus RCTL Protein
Within the numerous NK- and NKT-cell receptors, the c-type lectin-like NKP-
P1 family recognizes members of the Clr-family (Iizuka et al. 2003). Clr-b,
which is expressed on a wide range of cells, serves as a ligand for NKR-P1
(Carlyle et al. 2004). This interaction transmits an inhibitory NK cell signal.
Recently Hao et al. were able to show that infection with RCMV leads to a
nearly complete loss of Clr-b expression (Hao et al. 2006), which should nor-
mally lead to an enhanced susceptibility of the host cell to NK cell-mediated
killing. Interestingly, this is not the case. In vivo studies with a RCTL knockout
mutant of RCMV further showed that the virus displays a diminished virulence
in a strain-dependent manner controlled by host NKR-P1 polymorphism (Voigt
et al. 2007). RCTL exhibits homology to Clr-b (Voigt et al. 2001; Mesci et al.
2006), and it is most likely that it serves as a decoy for NKR-P1, sustaining the
inhibitory NK cell signaling.
Perspectives
CMVs encode more than 100 genes that are nonessential for growth in vitro (Yu
et al. 2003) and hence are likely to modulate the virus-host interaction in vivo. This
list includes all of the immune modulatory genes discussed here, but also a number
of genes with unknown function. Thus, one of the continuing goals of research in
immune modulation of HCMV will be to determine the function of nonessential
ORFs. However, defining the effects of unknown ORFs on the host cell or host
organisms can be daunting, particularly since HCMV does not infect immunocom-
petent animals. These obstacles can be, at least partially, overcome by using high
throughput technologies to identify host protein interacting with or destroyed by
CMV ORFs. Examples are quantitative proteomics technologies (Bartee et al.
2006), yeast two-hybrid screening (Uetz et al. 2006), or protein profiling using TAP
tags (Holowaty et al. 2003). Additional information can be obtained by studying the
role of homologous ORFs in murine, rat, and rhesus CMV in acute and latent infec-
tion. Since many of the HCMV immune modulators have homologs in the RhCMV
genome, this emerging model will be particularly useful to provide new information
on unknown ORFs. In addition, the RhCMV model will be used to study the func-
tion of homologs of HCMV immune modulators with known functions in vitro, but
not in vivo (Lockridge et al. 2000; Pande et al. 2005).
The demonstration that viral microRNAs (miRs) inhibit the expression of the
NKG2D-ligand MicB (Stern-Ginossar et al. 2007) recently also implicated noncod-
ing parts of the viral genome in immune evasion. Since HCMV encodes a panel of
miRs (see the chapter by P.J.F Rider et al., this volume), it can be expected that
additional host cell miR targets involved in immune stimulation will be discovered.
Thus, the immune evasion toolbox of CMVs still holds many surprises.
