Universität zu Köln

Franzoso, Francesca D., Seyffert, Michael ORCID: 0000-0001-7483-2430, Vogel, Rebecca, Yakimovich, Artur, Pereira, Bruna de Andrade, Meier, Anita F., Sutter, Sereina O., Tobler, Kurt, Vogt, Bernd, Greber, Urs F., Buening, Hildegard, Ackermann, Mathias and Fraefel, Cornel ORCID: 0000-0001-7221-6706 (2017). Cell Cycle-Dependent Expression of Adeno-Associated Virus 2 (AAV2) Rep in Coinfections with Herpes Simplex Virus 1 (HSV-1) Gives Rise to a Mosaic of Cells Replicating either AAV2 or HSV-1. J. Virol., 91 (15). WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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Abstract

Adeno-associated virus 2 (AAV2) depends on the simultaneous presence of a helper virus such as herpes simplex virus 1 (HSV-1) for productive replication. At the same time, AAV2 efficiently blocks the replication of HSV-1, which would eventually limit its own replication by diminishing the helper virus reservoir. This discrepancy begs the question of how AAV2 and HSV-1 can coexist in a cell population. Here we show that in coinfected cultures, AAV2 DNA replication takes place almost exclusively in S/G(2)-phase cells, while HSV-1 DNA replication is restricted to G(1) phase. Live microscopy revealed that not only wild-type AAV2 (wtAAV2) replication but also reporter gene expression from both single-stranded and double-stranded (self-complementary) recombinant AAV2 vectors preferentially occurs in S/G(2)-phase cells, suggesting that the preference for S/G(2) phase is independent of the nature of the viral genome. Interestingly, however, a substantial proportion of S/G(2)-phase cells transduced by the double-stranded but not the single-stranded recombinant AAV2 vectors progressed through mitosis in the absence of the helper virus. We conclude that cell cycle-dependent AAV2 rep expression facilitates cell cycle-dependent AAV2 DNA replication and inhibits HSV-1 DNA replication. This may limit competition for cellular and viral helper factors and, hence, creates a biological niche for either virus to replicate. IMPORTANCE Adeno-associated virus 2 (AAV2) differs from most other viruses, as it requires not only a host cell for replication but also a helper virus such as an adenovirus or a herpesvirus. This situation inevitably leads to competition for cellular resources. AAV2 has been shown to efficiently inhibit the replication of helper viruses. Here we present a new facet of the interaction between AAV2 and one of its helper viruses, herpes simplex virus 1 (HSV-1). We observed that AAV2 rep gene expression is cell cycle dependent and gives rise to distinct time-controlled windows for HSV-1 replication. High Rep protein levels in S/G(2) phase support AAV2 replication and inhibit HSV-1 replication. Conversely, low Rep protein levels in G(1) phase permit HSV-1 replication but are insufficient for AAV2 replication. This allows both viruses to productively replicate in distinct sets of dividing cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Franzoso, Francesca D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seyffert, Michael UNSPECIFIED orcid.org/0000-0001-7483-2430 UNSPECIFIED Vogel, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Yakimovich, Artur UNSPECIFIED UNSPECIFIED UNSPECIFIED Pereira, Bruna de Andrade UNSPECIFIED UNSPECIFIED UNSPECIFIED Meier, Anita F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sutter, Sereina O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tobler, Kurt UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Greber, Urs F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ackermann, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Fraefel, Cornel UNSPECIFIED orcid.org/0000-0001-7221-6706 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-224160
DOI:	10.1128/JVI.00357-17
Journal or Publication Title:	J. Virol.
Volume:	91
Number:	15
Date:	2017
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE-RESPONSE; BIOCHEMICAL-CHARACTERIZATION; HOMOLOGOUS RECOMBINATION; TYPE-1 REPLICATION; PROTEIN-KINASE; SITE; INTEGRATION; INHIBITION; HELICASE; ADENOVIRUS Multiple languages Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22416