Transplacental Infection with Adeno-Associated Virus Type 1 in Mice

Lipps, B. V.; Mayor, Heather D.

doi:10.1159/000149172

Cited by 17 publications

(10 citation statements)

References 14 publications

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“…Further supporting vertical transmission, transplacental transmission of avian AAV has been experimentally demonstrated in mice [Lipps & Mayor, 1980.…”

Section: Transmission and Reservoirmentioning

confidence: 86%

Evaluation of Risks Related to the Use of Adeno-Associated Virus-Based Vectors

Tenenbaum¹,

Lehtonen²,

Monahan³

2003

CGT

132

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Recombinant AAV efficacy has been demonstrated in numerous gene therapy preclinical studies. As this vector is increasingly applied to human clinical trials, it is a priority to evaluate the risks of its use for workers involved in research and clinical trials as well as for the patients and their descendants. At high multiplicity of infection, wild-type AAV integrates into human chromosome 19 in approximately 60% of latently infected cell lines. However, it has been recently demonstrated that only approximately 1 out of 1000 infectious units can integrate. The mechanism of this site-specific integration involves AAV Rep proteins which are absent in vectors. Accordingly, recombinant AAV (rAAV) do not integrate site-specifically. Random integration of vector sequences has been demonstrated in established cell lines but only in some cases and at low frequency in primary cultures and in vivo. In contrast, episomal concatemers predominate.Therefore, the risks of insertional mutagenesis and activation of oncogenes are considered low. Biodistribution studies in non-human primates after intramuscular, intrabronchial, hepatic artery and subretinal administration showed low and transient levels of vector DNA in body fluids and distal organs. Analysis of patients body fluids revealed rAAV sequences in urine, saliva and serum at short-term. Transient shedding into the semen has been observed after delivery to the hepatic artery. However, motile germ cells seemed refractory to rAAV infection even when directly exposed to the viral particles, suggesting that the risk of insertion of new genetic material into the germ line is absent or extremely low. Risks related to viral capsid-induced inflammation also seem to be absent since immune response is restricted to generation of antibodies. In contrast, transgene products can elicit both cellular and humoral immune responses, depending on the nature of the expressed protein and of the route of vector administration. Finally, a correlation between early abortion as well as male infertility and the presence of wt AAV DNA in the genital tract has been suggested. Although no causal relationship has been established, this issue stresses the importance of using rAAV stocks devoid of contaminating replication-competent AAV. This review comprehensively examines virus integration, biodistribution, immune interactions, and other safety concerns regarding the wild-type AAV and recombinant AAV vectors.

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“…Further supporting vertical transmission, transplacental transmission of avian AAV has been experimentally demonstrated in mice [Lipps & Mayor, 1980.…”

Section: Transmission and Reservoirmentioning

confidence: 86%

Evaluation of Risks Related to the Use of Adeno-Associated Virus-Based Vectors

Tenenbaum¹,

Lehtonen²,

Monahan³

2003

CGT

132

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“…AAV-2 also decreases adenovirus cytotoxicity and production in cell culture. In animal studies of AAV infection, AAV-1 was detected in kidneys and lungs of fetuses and newborns, when pregnant mice were injected subcutaneously with AAV-1 and murine adenovirus (Lipps and Mayor, 1980). However, mice carrying AAV-1 acquired via the transplacental route were protected against lethal infection by MAV (Lipps and Mayor, 1982).…”

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus infection of murine fibroblasts with help provided by mouse adenovirus

Bhrigu

Trempe

2009

Virology

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Adeno-associated virus (AAV-2) replicates to high titers when host cells are coinfected with a helper virus. Here we analyzed the coinfection of AAV-2 and mouse adenovirus (MAV-1) in murine fibroblasts. We observed that AAV-2/MAV-1 coinfected NIH 3T3 cells produced approximately 10-40-fold less AAV-2 DNAse resistant particles than Hela cells. Levels of AAV-2 DNA replication were approximately 30-fold less in 3T3 cells as compared to Hela cells coinfected with human adenovirus (Ad-5). A study of these lower levels of infection in 3T3 cells compared to Hela cells revealed that receptor binding and internalization of AAV-2 in 3T3 and Hela cells was comparable. However, AAV-2 did not enter into the nucleus of mouse cells as efficiently as it does in human cells. Furthermore, viral DNA replication levels of AAV-2 DNA were found to be lower in mouse cells than human cells, indicating limitations in the murine nucleus for viral replication.

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“…Condyloma is a manifestation of human papillomavirus (HPV) infection, which might have served as a helper virus in that case. Anecdotal reports have demonstrated the isolation of AAV from embryos, but no evidence exists to suggest that AAV infection presents a clinical problem in the pregnant human female population (Lipps and Mayor, 1980;Malhomme et al, 1997).…”

Section: Consequences Of Aav Infectionmentioning

confidence: 99%