Biology Reference
In-Depth Information
tegument proteins; (3) the cell cycle stage of the cell; and (4) the amounts of
silencing factors, such as HDAC, and repressors, such as Daxx, Sp100 and PML.
Those factors are likely to affect the immediate early transcription and specifically
the production of the major immediate early proteins. Success at the margin
appears to depend on the amount of IE1 produced to overcome such repressive
properties of the cell in a cell culture environment. Thus, IE1 plays a critical role
at the start of infection and might prove to be a target for antiviral drug develop-
ment. In order to assess the potential of IE1 as a drug development candidate, we
need to determine its influence on viral success in an organismal context.
Additionally, we do not know the mechanism of ND10 dispersion and the effect
of the release of ND10-associated proteins. The mechanism may be due to des-
umofication and as such IE1 may be a desumoylation enzyme. Such a function
needs to be directly searched for since it may affect more than ND10-associated
proteins presently recognized. The release of ND10-associated proteins by IE1
may mimic interferon upregulation of these proteins (PML and Sp100), i.e., sudden
availability of additional and in general detrimental proteins, we know now to be
specifically segregated and thus inactivated. Interferon downstream effects of
Sp100 as the intermediary protein are preliminarily associated with specific
inflammation-inducing proteins. Their occasional induction by abortively reacti-
vating latent virus may account for the atherosclerotic association of HCMV
despite never finding replicating virus in plaques.
Low priority has been given to splicing of the major immediate early transcrip-
tion unit. Exon skipping is involved, and how this is regulated will have a major
impact on reactivation. We expect to find cellular defense mechanisms that work
at the level of splicing inhibitors. A priori they must exist, since many cells may
reactivate to produce only IE1 but not IE2 or the MCMV IE3. The splice enhancers
and silencers in the nucleotide sequence will be difficult to identify, but it may be
essential to do so, so that when mutant viruses are produced with deletions in exon
4 to 5 for in vivo verification of IE1 or IE2 effects, we do not inadvertently assay
a splice phenomenon.
References
Ahn JH, Hayward GS (1997) The major immediate-early proteins IE1 and IE2 of human cytome-
galovirus colocalize with and disrupt PML-associated nuclear bodies at very early times in
infected permissive cells. J Virol 71:4599-4613
Ahn JH, Brignole EJ 3rd, Hayward GS (1998) Disruption of PML subnuclear domains by the
acidic IE1 protein of human cytomegalovirus is mediated through interaction with PML and
may modulate a RING finger-dependent cryptic transactivator function of PML. Mol Cell Biol
18:4899-4913
Bell P, Montaner LJ, Maul GG (2001) Accumulation and intranuclear distribution of unintegrated
human immunodeficiency virus type 1 DNA. J Virol 75:7683-7691
Berube NG, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons RJ, Higgs DR, Slack RS,
Picketts DJ (2005) The chromatin-remodeling protein ATRX is critical for neuronal survival
during corticogenesis. J Clin Invest 115:258-267
