Definition of Herpes Simplex Virus Type 1 Helper Activities for Adeno-Associated Virus Early Replication Events

Alazard-Dany, Nathalie; Nicolas, Armel; Ploquin, Aurélie; Strasser, Regina; Greco, Anna; Epstein, Alberto L.; Fraefel, Cornel; Salvetti, Anna

doi:10.1371/journal.ppat.1000340

Cited by 44 publications

(71 citation statements)

References 45 publications

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“…Activation of the p5 promoter by ICP0 also involves the interaction of ICP0 with the deubiquitylating enzyme USP7/HAUSP, which, however, is not essential [135,137]. It was recently shown that transactivation of rep expression by ICP0 can be further enhanced by the presence of two other HSV-1 IE proteins, ICP4 and ICP22 [138]. On their own, ICP4 stimulates rep expression only marginally, while ICP22 has no effect [138].…”

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

“…It was recently shown that transactivation of rep expression by ICP0 can be further enhanced by the presence of two other HSV-1 IE proteins, ICP4 and ICP22 [138]. On their own, ICP4 stimulates rep expression only marginally, while ICP22 has no effect [138]. ICP4 is a transactivator protein essential for HSV-1 replication and is required for expression of several early and late genes [139].…”

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

“…ICP22 stimulates the expression of some HSV-1 late genes and is involved in the alteration of cell-cycle regulatory proteins and in the modification of cellular RNA polymerase II [142,143]. The molecular mechanism by which ICP22 contributes to transactivation of rep expression remains, however, unknown [138]. rep expression from AAV-2 genomes delivered into the cell by infection or transfection is less tightly repressed than that of AAV-2 genomes integrated into the host cell genome.…”

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

“…rep expression from AAV-2 genomes delivered into the cell by infection or transfection is less tightly repressed than that of AAV-2 genomes integrated into the host cell genome. Consequently, low-level rep expression can be observed even in the absence of helper virus, which is, however, significantly enhanced by the presence of ICP0, ICP4 and ICP22 [138]. AAV-2 replication upon infection or transfection is therefore much less dependent on rep transactivation by ICP0, ICP4 and ICP22 than reactivation of latent virus [138,144].…”

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

“…Simultaneously, the large Rep proteins initiate AAV-2 DNA replication by binding to the RBSs in the ITR and p5 oris followed by nicking at the TRSs, the latter creating primers for repair synthesis of the ITRs [145]. It is at this stage of its replication cycle that AAV-2 again depends on help from HSV-1, specifically the presence of the ssDNA-binding protein ICP8 (encoded by UL29), the helicase-primase complex (encoded by UL5, UL8 and UL52) and the DNA polymerase holoenzyme (encoded by UL30 and UL42) [138]. It is thought that during AAV-2-HSV-1 coinfection, the AAV-2 DNA is replicated by the HSV-1 replication machinery assembling on the AAV-2 oris [120].…”

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

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Interactions Between AAV-2 and HSV-1: Implications for Hybrid Vector Design

Glauser

Fraefel

2011

Future Virol.

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Herpes simplex virus type 1 (HSV-1)-based amplicon vectors have a transgene capacity of up to 150 kbp and can efficiently transduce many different cell types in culture and in vivo without causing cytopathic effects. However, these vectors do not support long-term transgene expression. Adeno-associated virus type 2 (AAV-2) has the capacity to integrate its genome into a specific site on human chromosome 19, but AAV-2-derived gene therapy vectors have a transgene capacity of only 4.5 kb. To combine the large transgene capacity of HSV-1 with the potential for site-specific genomic integration and long-term transgene expression of AAV-2, HSV/AAV hybrid vectors have been developed. This review describes the design, applications and limitations of these hybrid vectors. However, as HSV-1 is a full helper virus for AAV-2 replication, the main focus is the analysis of the molecular mechanisms of interaction between the two viruses. The knowledge of these interactions will have direct implications on the design of novel HSV/AAV hybrid vectors.

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Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

Section: Hsv-1-based Gene Therapy Vectorsmentioning

confidence: 99%

See 3 more Smart Citations

Interactions Between AAV-2 and HSV-1: Implications for Hybrid Vector Design

Glauser

Fraefel

2011

Future Virol.

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Tuning capsid formation dynamics in recombinant adeno‐associated virus producing synthetic cell lines to enhance full particle productivity

Lu,

Lin,

Kuo

et al. 2024

Biotechnology Journal

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Recombinant adeno‐associated virus (rAAV) is widely used as an in vivo delivery vector for gene therapy. It is used in a very large dose, and the large quantities required for broad applications present manufacturing challenges. We have developed a synthetic biology platform of constructing cell lines integrated with essential viral genes which can be induced to produce rAAV without plasmid transfection or virus transduction. Through iterative design‐construct‐characterization cycles, we have showcased the potential of this synthetic cell production system. Systems characterization of the dynamics of viral transcripts and proteins as well as virus assembly and packaging revealed that the expression level and balance of viral genome and capsid protein are keys to not only the productivity but also the full particle content, an important product quality attribute. Boosting cap gene expression by sequential transfection and integration of multiple copies of the cap gene elevated the rAAV titer to levels on a par with traditional plasmid transfection and virus infection. However, overexpression of the cap gene shifted the balance and kinetics of the genome and capsid. We independently tuned the dynamics of genome amplification and capsid protein synthesis by modulating the induction concentration as well as the time profile, and significantly enhanced full particle content while maintaining a high productivity. This strategy of constructing an inducible stable producer cell line is readily adaptable to rAAV vectors of different serotypes and payloads. It can greatly facilitate scalable production of gene therapy vectors.

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Comprehensive analysis of liquid–liquid phase separation propensities of HSV‐1 proteins and their interaction with host factors

Subedi,

Nag,

Shukla

et al. 2023

J of Cellular Biochemistry

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In recent years, it has been shown that the liquid–liquid phase separation (LLPS) of virus proteins plays a crucial role in their life cycle. It promotes the formation of viral replication organelles, concentrating viral components for efficient replication and facilitates the assembly of viral particles. LLPS has emerged as a crucial process in the replication and assembly of herpes simplex virus‐1 (HSV‐1). Recent studies have identified several HSV‐1 proteins involved in LLPS, including the myristylated tegument protein UL11 and infected cell protein 4; however, a complete proteome‐level understanding of the LLPS‐prone HSV‐1 proteins is not available. We provide a comprehensive analysis of the HSV‐1 proteome and explore the potential of its proteins to undergo LLPS. By integrating sequence analysis, prediction algorithms and an array of tools and servers, we identified 10 HSV‐1 proteins that exhibit high LLPS potential. By analysing the amino acid sequences of the LLPS‐prone proteins, we identified specific sequence motifs and enriched amino acid residues commonly found in LLPS‐prone regions. Our findings reveal a diverse range of LLPS‐prone proteins within the HSV‐1, which are involved in critical viral processes such as replication, transcriptional regulation and assembly of viral particles. This suggests that LLPS might play a crucial role in facilitating the formation of specialized viral replication compartments and the assembly of HSV‐1 virion. The identification of LLPS‐prone proteins in HSV‐1 opens up new avenues for understanding the molecular mechanisms underlying viral pathogenesis. Our work provides valuable insights into the LLPS landscape of HSV‐1, highlighting potential targets for further experimental validation and enhancing our understanding of viral replication and pathogenesis.

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Definition of Herpes Simplex Virus Type 1 Helper Activities for Adeno-Associated Virus Early Replication Events

Cited by 44 publications

References 45 publications

Interactions Between AAV-2 and HSV-1: Implications for Hybrid Vector Design

Interactions Between AAV-2 and HSV-1: Implications for Hybrid Vector Design

Tuning capsid formation dynamics in recombinant adeno‐associated virus producing synthetic cell lines to enhance full particle productivity

Comprehensive analysis of liquid–liquid phase separation propensities of HSV‐1 proteins and their interaction with host factors

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