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A number of important and exciting questions remain:
1. How does HCMV infection activate PI3K? Initially, viral attachment to receptors
may transiently activate PI3K but later in the infection viral protein synthesis is
required. The observation that the major immediate early proteins (IE1 and IE2)
can mediate PI3K activation suggests a mechanism involving transcriptional activa-
tion of viral or cellular genes, the products of which may activate PI3K.
However, IE1 and IE2, being complex proteins, may mediate functions, such as
the activation of PI3K, which do not depend on transcriptional mechanisms.
2. How are mTORC1 and mTORC2 altered such that their rapamycin sensitivities
are reversed and mTORC2 gains 4E-BP and S6K as substrates? Structural modi-
fications of the complexes have been discussed above. It is clearly possible that
a cellular protein, induced or misplaced by the viral infection, or a viral protein,
becomes part of the complexes and alters their specificities and functions.
Indeed, it is conceivable that mTOR is not the only kinase associated with raptor
and rictor in infected cells. The shRNA-mediated depletion of mTOR kinase in
HCMV infected cells significantly decreases but does not eliminate 4E-BP and
S6K phosphorylation (Kudchodkar et al. 2006), thus another kinase could be
active with rictor and raptor in infected cells.
3. What mechanism is HCMV using to trigger mTORC2-mediated phosphoryla-
tion of Akt S473? As mentioned above in Sect. 3, the control of mTORC2 activ-
ity is not well understood. One study suggests that Rheb-GTP, the activator of
mTORC1, may inhibit mTORC2 (Yang et al. 2006b). If this is correct, the inhibi-
tion of the TSC by pUL38 would be expected to increase Rheb-GTP levels and
potentially inhibit mTORC2. However, this does not happen: the rapamycin
insensitive phosphorylation of Akt S473 by mTORC2 is activated during an
HCMV infection (Kudchodkar et al. 2006). Hence there is still much to learn
about HCMV's effects of mTORC2 and the phosphorylation of Akt.
In the above discussion, we have not considered the potential role of phos-
phatases in the control of the PI3K-Akt-mTOR pathway. PTEN (phosphatase and
tensin homolog) is the phosphatase that counteracts PI3K (Baker 2007); its inhibi-
tion during infection could account, in part, for the activation of Akt. In human
fibroblasts, PTEN levels do not change during infection (Y. Yu and J.C. Alwine,
unpublished observations), but it has not been determined whether its activity is
altered. One report suggests that PTEN activity may be increased in primary human
aortic endothelial cells infected with HCMV (Shen et al. 2006). This could reduce
Akt activation and slow the growth of HCMV in these specialized cells, possibly
resulting in specific pathogenesis. Protein phosphatase 2A (PP2A) is believed to be
the phosphatase that counteracts mTOR kinase by dephosphorylating 4E-BP and
S6K. Indeed, PP2A is a central controlling factor in many cellular processes
(Mumby 2007). Little is known about the HCMV's interactions with PP2A, but it
is likely to be an HCMV target.
Finally, our discussion has largely used the maintenance of cap-dependent
translation as the main reason for HCMV targeting the PI3K-Akt-mTOR pathway.
However, this is a narrow view. The many interactions that HCMV has with this
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