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 recently identified system of viral restriction is the Apolipoprotein B editing complex (APOBEC or A) family of proteins. Human APOBEC3G was first identified as an anti-viral factor in HIV infection. The human genome encodes multiple A3 proteins, including hA3G and hA3F. hA3G and hA3F restrict infection by Vif-deficient human immunodeficiency virus 1 (HIV-1). A3 proteins are packaged into virions and inhibit retroviral replication in newly infected cells, in part by deaminating cytosines on negative strand DNA intermediates and through as of yet uncharacterized mechanisms. We recently provided the first in vivo demonstration of an antiviral function for A3 proteins. We showed that mouse mammary tumor virus (MMTV) replication was inhibited by endogenous mA3 in vivo, since mice with targeted deletion of this gene were more susceptible to infection than their wild type littermates. We also showed that hA3G was packaged into MMTV virions and inhibited infection of cultured cells. We propose here to use MMTV to further probe the function of mA3 and hA3 proteins. We will examine the mechanism by which A3 proteins are packaged into virions, restrict retrovirus infection in vitro and in vivo, the role that polymorphisms in the A3 genes plays in affecting virus restriction and whether A3 expression in mammary tissue restricts milk-borne transmission of virus. As a consequence of these studies, we will know what role/s A3 proteins play in infection by exogenous viruses. These studies will provide a basis for understanding how this family of intrinsic immune factors inhibits viral infection of the mouse and other species by exogenous viruses, including HIV-1 infection of humans.

Public Health Relevance

This project will investigate a newly discovered anti-viral host restriction factor, APOBEC3, which inhibits HIV-1 infection. Our experiments will take advantage of a unique mouse model developed by our lab to examine the role of APOBEC3 in restricting infection by the murine retrovirus mouse mammary tumor virus in vivo. These studies will provide insight into how APOBEC3 proteins inhibit infection by human retroviruses such as HIV-1 in an experimentally tractable mouse model.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Park, Eun-Chung
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University of Pennsylvania
Schools of Medicine
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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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