Research Article: Different Modes of Retrovirus Restriction by Human APOBEC3A and APOBEC3G In Vivo

Date Published: May 22, 2014

Publisher: Public Library of Science

Author(s): Spyridon Stavrou, Daniel Crawford, Kristin Blouch, Edward P. Browne, Rahul M. Kohli, Susan R. Ross, Michael H. Malim.

http://doi.org/10.1371/journal.ppat.1004145

Abstract

The apolipoprotein B editing complex 3 (A3) cytidine deaminases are among the most highly evolutionarily selected retroviral restriction factors, both in terms of gene copy number and sequence diversity. Primate genomes encode seven A3 genes, and while A3F and 3G are widely recognized as important in the restriction of HIV, the role of the other genes, particularly A3A, is not as clear. Indeed, since human cells can express multiple A3 genes, and because of the lack of an experimentally tractable model, it is difficult to dissect the individual contribution of each gene to virus restriction in vivo. To overcome this problem, we generated human A3A and A3G transgenic mice on a mouse A3 knockout background. Using these mice, we demonstrate that both A3A and A3G restrict infection by murine retroviruses but by different mechanisms: A3G was packaged into virions and caused extensive deamination of the retrovirus genomes while A3A was not packaged and instead restricted infection when expressed in target cells. Additionally, we show that a murine leukemia virus engineered to express HIV Vif overcame the A3G-mediated restriction, thereby creating a novel model for studying the interaction between these proteins. We have thus developed an in vivo system for understanding how human A3 proteins use different modes of restriction, as well as a means for testing therapies that disrupt HIV Vif-A3G interactions.

Partial Text

Retroviruses are enveloped RNA viruses that infect many different species including humans. The constant “battle” between retroviruses and mammalian cells has resulted in the evolution of proteins that act as cellular restriction factors. These restriction factors provide defense against retroviruses by blocking various points of the retroviral life cycle within the cell [1], [2].

A3 family members play important roles in the host’s defense against viral infections, in particular against retroviruses. While much is known about the function of human A3 proteins in vitro, less is known about their function in vivo. In contrast, studies in A3 knock-out mice infected with various murine retroviruses have begun to elucidate the role of these proteins during in vivo infection [32], [33], [41]. Here we took advantage of mA3 knockout mice and generated transgenic mice that express human A3G and A3A in the absence of mouse A3, with the goal of developing a system with which to study the in vivo effects of individual human proteins. Primates express 7 A3 proteins, many with overlapping target motif sites. Due to the common target motif sites, it is difficult to fully discriminate the contribution of each A3 protein to inhibiting retrovirus infection in vivo or in primary cells. The development of transgenic mice that express only one A3 protein allows us to delineate the function of each A3 protein in vivo without the interference of the other A3 proteins.

 

Source:

http://doi.org/10.1371/journal.ppat.1004145

 

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