The Role of DNA Repair Pathways in Adeno-Associated Virus Infection and Viral Genome Replication / Recombination / Integration

Adachi, Kei; Nakai, Hiroyuki

doi:10.5772/24265

Cited by 6 publications

(7 citation statements)

References 148 publications

(203 reference statements)

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“…Although effects such as cell cycle arrest and apoptosis were observed during expression of the large Rep proteins and infection of UV-inactivated AAV, little is known about the impact of DDR signaling on the fate of host cells and the life cycle of AAV2 during coinfection with its helper viruses. Nevertheless, study of AAV2-induced DDR will help us to better understand the biology of AAVs for enhancing rAAV transduction and preventing the potential hazards of using AAV vectors in human gene therapy [89]. …”

Section: Genus Dependovirus (Aav2)mentioning

confidence: 99%

Parvovirus Infection-Induced DNA Damage Response

Luo

Qiu

2013

Future Virol.

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Parvoviruses are a group of small DNA viruses with ssDNA genomes flanked by two inverted terminal structures. Due to a limited genetic resource they require host cellular factors and sometimes a helper virus for efficient viral replication. Recent studies have shown that parvoviruses interact with the DNA damage machinery, which has a significant impact on the life cycle of the virus as well as the fate of infected cells. In addition, due to special DNA structures of the viral genomes, parvoviruses are useful tools for the study of the molecular mechanisms underlying viral infection-induced DNA damage response (DDR). This review aims to summarize recent advances in parvovirus-induced DDR, with a focus on the diverse DDR pathways triggered by different parvoviruses and the consequences of DDR on the viral life cycle as well as the fate of infected cells.

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Section: Genus Dependovirus (Aav2)mentioning

confidence: 99%

Parvovirus Infection-Induced DNA Damage Response

Luo

Qiu

2013

Future Virol.

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“…Particular motifs and secondary structures within AAV ITR may have a significant impact on gene transfer efficiency. Indeed, it has already been demonstrated that AAV2 ITRs are detected by cellular factors belonging to the NHEJ and HR-DNA damage pathways [37]. The viral telomeres may also be recognized by DNA sensors which subsequently could restrict AAV vectors transduction or activate innate immune responses [21].…”

Section: Gr-alpha [T00337]mentioning

confidence: 99%

The Diversity of Parvovirus Telomeres

Laugel¹,

Lecomte²,

Ayuso³

et al. 2023

Recent Advances in Canine Medicine

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Parvoviridae are small viruses composed of a 4–6 kb linear single-stranded DNA protected by an icosahedral capsid. The viral genes coding non-structural (NS), capsid, and accessory proteins are flanked by intriguing sequences, namely the telomeres. Telomeres are essential for parvovirus genome replication, encapsidation, and integration. Similar (homotelomeric) or different (heterotelomeric) at the two ends, they all contain imperfect palindromes that fold into hairpin structures. Up to 550 nucleotides in length, they harbor a wide variety of motifs and structures known to be recognized by host cell factors. Our study aims to comprehensively analyze parvovirus ends to better understand the role of these particular sequences in the virus life cycle. Forty Parvoviridae terminal repeats (TR) were publicly available in databases. The folding and specific DNA secondary structures, such as G4 and triplex, were systematically analyzed. A principal component analysis was carried out from the prediction data to determine variables signing parvovirus groups. A special focus will be put on adeno-associated virus (AAV) inverted terminal repeats (ITR), a member of the genus Dependoparvovirus used as vectors for gene therapy. This chapter highlights the diversity of the Parvoviridae telomeres regarding shape and secondary structures, providing information that could be relevant for virus-host interactions studies.

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“…AAV has been bioengineered to produce rAAV vectors to target diverse monogenic disorders, and many therapies are either approved or in late-stage development ( Table 2 ). In a rAAV vector, the AAV genome is replaced by a transgene expression cassette that includes a specialized promoter, transgene of interest, and transcriptional terminator, flanked with ITRs ( Figure 1 B ) 11 , 25 . In addition to accommodating a transgene expression cassette, this replacement of viral coding sequences contributes to lower immunogenicity and cytotoxicity ( Table 1 ) 11 .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to accommodating a transgene expression cassette, this replacement of viral coding sequences contributes to lower immunogenicity and cytotoxicity ( Table 1 ) 11 . The tissue tropism of the resultant rAAV is largely determined by the capsid used with a range of natural or engineered capsids available to target different tissues 11 , 14 , 25 . The selectivity and efficiency of transduction can be further enhanced by optimizing the transgene expression cassette through improved codon usage, CpG-depletion or with the inclusion of tissue- or cell-selective regulatory elements 11 , 26 , 27 .…”

Section: Introductionmentioning

confidence: 99%

Understanding AAV vector immunogenicity: from particle to patient

Dhungel,

Winburn,

Pereira

et al. 2024

Theranostics

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Gene therapy holds promise for patients with inherited monogenic disorders, cancer, and rare genetic diseases. Naturally occurring adeno-associated virus (AAV) offers a well-suited vehicle for clinical gene transfer due to its lack of significant clinical pathogenicity and amenability to be engineered to deliver therapeutic transgenes in a variety of cell types for long-term sustained expression. AAV has been bioengineered to produce recombinant AAV (rAAV) vectors for many gene therapies that are approved or in late-stage development. However, ongoing challenges hamper wider use of rAAV vector-mediated therapies. These include immunity against rAAV vectors, limited transgene packaging capacity, sub-optimal tissue transduction, potential risks of insertional mutagenesis and vector shedding. This review focuses on aspects of immunity against rAAV, mediated by anti-AAV neutralizing antibodies (NAbs) arising after natural exposure to AAVs or after rAAV vector administration. We provide an in-depth analysis of factors determining AAV seroprevalence and examine clinical approaches to managing anti-AAV NAbs pre- and post-vector administration. Methodologies used to quantify anti-AAV NAb levels and strategies to overcome pre-existing AAV immunity are also discussed. The broad adoption of rAAV vector-mediated gene therapies will require wider clinical appreciation of their current limitations and further research to mitigate their impact.

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The Role of DNA Repair Pathways in Adeno-Associated Virus Infection and Viral Genome Replication / Recombination / Integration

Cited by 6 publications

References 148 publications

Parvovirus Infection-Induced DNA Damage Response

Parvovirus Infection-Induced DNA Damage Response

The Diversity of Parvovirus Telomeres

Understanding AAV vector immunogenicity: from particle to patient

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