Role of rhesus macaque IFITM3(2) in simian immunodeficiency virus infection of macaques.

Michael Winkler,Stefan Pöhlmann,Inga Nehlmeier,Lara Markus,Ulrike Sauermann,Markus Hoffmann,Michael Krawczak,Sabine Gärtner

doi:10.1371/journal.pone.0224082

Abstract

The experimental infection of rhesus macaques (rh) with simian immunodeficiency virus (SIV) is an important model for human immunodeficiency virus (HIV) infection of humans. The interferon-induced transmembrane protein 3 (IFITM3) inhibits HIV and SIV infection at the stage of host cell entry. However, it is still unclear to what extent the antiviral activity of IFITM3 observed in cell culture translates into inhibition of HIV/SIV spread in the infected host. We have shown previously that although rhIFITM3 inhibits SIV entry into cultured cells, polymorphisms in the rhIFITM3 gene are not strongly associated with viral load or disease progression in SIV infected macaques. Here, we examined whether rhIFITM3(2), which is closely related to rhIFITM3 at the sequence level, exerts antiviral activity and whether polymorphisms in the rhIFITM3(2) gene impact the course of SIV infection. We show that expression of rhIFITM3(2) is interferon-inducible and inhibits SIV entry into cells, although with reduced efficiency as compared to rhIFITM3. We further report the identification of 19 polymorphisms in the rhIFITM3(2) gene. However, analysis of a well characterized cohort of SIV infected macaques revealed that none of the polymorphisms had a significant impact upon the course of SIV infection. These results and our previous work suggest that polymorphisms in the rhIFITM3 and rhIFITM3(2) genes do not strongly modulate the course of SIV infection in macaques.

Highlights

The interferon (IFN) system is an integral component of innate immunity and constitutes the first line of defense against viral infection
We examined particles harboring the envelope protein (Env) protein of murine leukemia virus (MLV) or the hemagglutinin (HA) of factors modulating influenza A virus (FLUAV), because it is well known that MLV Env-driven entry is largely resistant to inhibition by IFN-induced transmembrane protein 3 (IFITM3) while FLUAV-HA-mediated entry is highly sensitive [3, 4]
Human patients harboring a particular polymorphism in the huIFITM3 gene, rs12252-C, which results in the alteration of a splice acceptor site, were previously shown to be more susceptible to severe influenza than non-carrier patients [10, 36]

Summary

Introduction

The interferon (IFN) system is an integral component of innate immunity and constitutes the first line of defense against viral infection. The antiviral effect of the IFN response is due to the IFN-induced expression of approximately 400 genes, many of which encode proteins that exert antiviral activity [1, 2]. The IFN-induced transmembrane protein 3 (IFITM3) was identified in a screen for host cell factors modulating influenza A virus (FLUAV) infection [3] and inhibits host cell entry of FLUAV and several other viral pathogens [3,4,5]. Intact IFITM3 is essential for defense against severe influenza [9, 10], indicating the protein exerts potent antiviral activity in the infected host

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Results

Conclusion