Infectious agents have infected prokaryotes and eukaryotes throughout evolution. Indeed, there is co-evolution among organisms and their infectious agents, with development of protective responses in the hosts and adaptive countermeasures to them by the infectious agents. One system of viral restriction is conferred by the Apolipoprotein B editing complex 3 (A3) family of proteins, which deaminate deoxycytidine residues in single-stranded DNA leading to GC-to-AT transitions. A3 genes are highly polymorphic both with regard to copy number and sequence and show strong evidence of positive selection, indicating that they are evolving in response to infectious agents like viruses Similarly, retroviruses and other viruses show deamination footprints suggesting they in turn are under selective pressure by A3 proteins and it has been suggested that A3-mediated deamination of viral DNA could lead to both drug-resistant and immune escape variants. While much has been learned about A3 proteins and their roles in virus restriction, most studies have been carried out in cultured cells, often using over- expressed proteins and sequence analysis of viruses isolated from patient tissue or experiments in human primary cells are complicated by the presence of 7 human A3 genes, many of which are expressed in the same cell types. Indeed while A3B, A3D, A3F, A3G and A3H all restrict HIV and other viruses when over-expressed, there role in control of infection in vivo remains unclear. Our lab pioneered the use of in vivo mouse models to study how A3 proteins restrict infection by retroviruses. We have developed knockout mice and more recently genetically engineered animals that express individual human A3 proteins to study infection by mouse mammary tumor virus and murine leukemia virus. Here, we propose to use these mouse models to study how individual human A3 proteins function in to restrict in vivo infection, shape virus evolution and affect the developmen of immune escape and drug-resistant retroviruses. These studies will thus add to our understanding of A3 proteins mechanism of action in vivo as well as provide models for testing anti-viral drug therapies.

Public Health Relevance

The 7 human APOBEC3 genes encode cytidine deaminases (CDAs) that are host intrinsic anti- viral restriction factors, inhibiting infection by a diverse aray of viruses including retroviruses like HIV. While these CDAs are critical to anti-viral immunity, they also have the potential to lead to drug-resistant and immune escape variants. This research will develop mouse models with which to better understand how the individual human APOBEC3 genes inhibit virus infection and in turn, how viruses evolve to evade this inhibition.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Virology - B Study Section (VIRB)
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Park, Eun-Chung
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University of Illinois at Chicago
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Stavrou, Spyridon; Zhao, Wenming; Blouch, Kristin et al. (2018) Deaminase-Dead Mouse APOBEC3 Is an In Vivo Retroviral Restriction Factor. J Virol 92:
Stavrou, Spyridon; Aguilera, Alexya N; Blouch, Kristin et al. (2018) DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for In Vivo Control of Murine Leukemia Virus Infection. MBio 9:
Nakaya, Yuki; Lilue, Jingtao; Stavrou, Spyridon et al. (2017) AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA. MBio 8:
Dudley, Jaquelin P; Golovkina, Tatyana V; Ross, Susan R (2016) Lessons Learned from Mouse Mammary Tumor Virus in Animal Models. ILAR J 57:12-23
Cadena, Cristhian; Stavrou, Spyridon; Manzoni, Tomaz et al. (2016) The effect of HIV-1 Vif polymorphisms on A3G anti-viral activity in an in vivo mouse model. Retrovirology 13:45
Nakaya, Yuki; Stavrou, Spyridon; Blouch, Kristin et al. (2016) In Vivo Examination of Mouse APOBEC3- and Human APOBEC3A- and APOBEC3G-Mediated Restriction of Parvovirus and Herpesvirus Infection in Mouse Models. J Virol 90:8005-12
Stavrou, Spyridon; Blouch, Kristin; Kotla, Swathi et al. (2015) Nucleic acid recognition orchestrates the anti-viral response to retroviruses. Cell Host Microbe 17:478-88
Stavrou, Spyridon; Ross, Susan R (2015) APOBEC3 Proteins in Viral Immunity. J Immunol 195:4565-70
Stavrou, Spyridon; Crawford, Daniel; Blouch, Kristin et al. (2014) Different modes of retrovirus restriction by human APOBEC3A and APOBEC3G in vivo. PLoS Pathog 10:e1004145
Stavrou, Spyridon; Nitta, Takayuki; Kotla, Swathi et al. (2013) Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex. Proc Natl Acad Sci U S A 110:9078-83

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