Novel mouse lines: A3 knockout mice transgenically expressing either A3A or A3G

Strain Information: Laboratory mouse transgenically expressing human APOBEC3A protein on an APOBEC3 null background.

The apolipoprotein B editing complex 3A – APOBEC3A or A3A – is one of seven members of the APOBEC3 family found in humans and other primates. The APOBEC3 family of cytidine deaminases function by removing amino groups from cytosine nucleotides on foreign DNA. Specifically, A3A confers innate immunity against retroviruses by interfering with their ability to replicate, and may also have additional capacity for viral restriction, independent of its cytidine deaminase activity (1). A3A is highly expressed in monocytes and macrophages upon stimulation with interferon and its expression is correlated with restriction of HIV-1 infection. In contrast to its paralog A3G, A3A is not packaged into HIV virions but instead functions to restrict viral infection by targeting viruses directly, primarily carrying out this function in sentinel cells of the immune system.

Type: Mutant strain; targeted deletion, transgenic addition

Mating System: Heterozygote x Heterozygote

Species: Laboratory mouse

Donating Investigator: Susan R. Ross PhD, University of Pennsylvania

Development: Transgenic mice were created by injecting purified DNA fragments containing myc-tagged human A3A, driven by the chicken B-actin regulatory region, into the fertilized eggs of C57BL/6 mice.  The resulting transgenic mice were then backcrossed with mice containing a target knock-out of the only murine A3 gene (2). The resulting progeny contain functional copies of only the human gene. These A3A transgenic mice are capable of restricting Moloney MLV and MMTV.

Advantages: Humanized A3A transgenic mice provide the first-ever system to study the role of human A3A cytidine deaminase in isolation, in vivo.  A3A cytidine deaminase is a crucial component of the innate immune response to multiple types of viruses.  These mice are useful in a variety of infectious models, and for preclinical development of anti-viral therapeutics, particularly those that rely on the modulation of A3A proteins such a HIV, and those viruses shown to be regulated by A3A activity; HPV, HBV, HSV, and parvovirus.

Publications: Stavrou, S., et al. PLoS Pathog. 2014 10(5):e1004245.

Reference Media:
 - Narvaiza, I., et al. PLos Pathog. 2009 5(5):e1000439.
 - Low, A., et al. Virology 2009 15; 385(2): 455.

Strain Information: Laboratory mouse transgenically expressing human APOBEC3G protein on an APOBEC3 null background.

The apolipoprotein B editing complex 3G – APOBEC3G or A3G – is one of seven members of the APOBEC3 family found in humans and other primates. The APOBEC3 family of cytidine deaminases function by removing amino groups from cytidine nucleotides on foreign single stranded DNA, converting them to uridine nucleotides. Specifically, A3G confers innate immunity against retroviruses by interfering with viral replication.  A3G is packaged into virions during retroviral assembly where it inhibits proper virion production and spread to other cells.  During HIV infection the vif protein interacts with A3G and results in its ubiquitylation and degradation by the proteasome, enhancing HIV replication.

Type: Mutant Strain; Targeted deletion, transgenic addition

Mating System: Heterozygote x Heterozygote

Species:  Laboratory Mouse

Donating Investigator:  Susan R. Ross PhD, University of Pennsylvania

Development: Transgenic mice were created by injecting purified DNA fragments containing myc-tagged human A3G, driven by the chicken B-actin regulatory region, into the fertilized eggs of C57BL/6 mice.  The resulting transgenic mice were then backcrossed with mice containing a target knock-out of the only murine A3 gene (1). The resulting progeny contain functional copies of only the human gene. These A3G transgenic mice are capable of restricting Moloney MLV and MMTV.

Advantages: Humanized A3G transgenic mice provide the first-ever system to study the role of human A3G cytidine deaminase in isolation, in vivo.  A3G cytidine deaminase is a crucial component of the innate immune response to multiple types of viruses.  The human A3G expressed in these mice is inhibited by HIV vif protein, providing a useful preclinical model for the development of small molecule inhibitors of the A3G, vif interaction.  In addition to HIV these mice are useful in a variety of infectious models including HPV, HBV, and HSV, and are well-suited for pre-clinical development of anti-viral therapeutics.

Publications: Stavrou, S., et al. PLoS Pathog. 2014 10(5):e1004245.

References: Low, A., et al. Virology 2009 March 15; 385(2): 455.

Patent Information:

Contact

Linara Axanova

Interim Director, PSOM Licensing Group
University of Pennsylvania

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Docket # 14-7078