Adeno-associated virus Rep represses the human integration site promoter by two pathways that are similar to those required for the regulation of the viral p5 promoter.
Journal of Virology. 2014-05-14; 88(15): 8227-8241
DOI: 10.1128/jvi.00412-14
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1. J Virol. 2014 Aug;88(15):8227-41. doi: 10.1128/JVI.00412-14. Epub 2014 May 14.
Adeno-associated virus Rep represses the human integration site promoter by two
pathways that are similar to those required for the regulation of the viral p5
promoter.
Dutheil N(1), Smith SC(1), Agúndez L(1), Vincent-Mistiaen ZI(1), Escalante CR(1),
Linden RM(1), Henckaerts E(2).
Author information:
(1)Department of Infectious Diseases, King’s College London School of Medicine,
London, United Kingdom.
(2)Department of Infectious Diseases, King’s College London School of Medicine,
London, United Kingdom .
Adeno-associated virus serotype 2 (AAV2) can efficiently replicate in cells that
have been infected with helper viruses, such as adenovirus or herpesvirus.
However, in the absence of helper virus infection, AAV2 establishes latency by
integrating its genome site specifically into PPP1R12C, a gene located on
chromosome 19. This integration target site falls into one of the most gene-dense
regions of the human genome, thus inviting the question as to whether the virus
has evolved mechanisms to control this complex transcriptional environment in
order to facilitate integration, maintain an apparently innocuous latency, and/or
establish conditions that are conducive to the rescue of the integrated viral
genome. The viral replication (Rep) proteins control and direct every known
aspect of the viral life cycle and have been shown to tightly control all AAV2
promoters. In addition, a number of heterologous promoters are repressed by the
AAV2 Rep proteins. Here, we demonstrate that Rep proteins efficiently repress
expression from the target site PPP1R12C promoter. We find evidence that this
repression employs mechanisms similar to those described for Rep-mediated AAV2 p5
promoter regulation. Furthermore, we show that the repression of the cellular
target site promoter is based on two distinct mechanisms, one relying on the
presence of a functional Rep binding motif within the 5′ untranslated region
(UTR) of PPP1R12C, whereas the second pathway requires only an intact nucleoside
triphosphate (NTP) binding site within the Rep proteins, indicating the possible
reliance of this pathway on interactions of the Rep proteins with cellular
proteins that mediate or regulate cellular transcription.IMPORTANCE: The
observation that repression of transcription from the adeno-associated virus
serotype 2 (AAV2) p5 and integration target site promoters is mediated by shared
mechanisms highlights the possible coevolution of virus and host and could lead
to the identification of host factors that the virus exploits to navigate its
life cycle.
Copyright © 2014 Dutheil et al.
DOI: 10.1128/JVI.00412-14
PMCID: PMC4135950
PMID: 24829354 [Indexed for MEDLINE]