Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5α-induced inhibition of human immunodeficiency virus type-1 production.

Sayaka Sukegawa,Ryuta Sakuma,Hiroaki Takeuchi,Yasuhiro Ikeda,Seiga Ohmine,Shoji Yamaoka,Mario L Santiago

doi:10.1371/journal.pone.0109640

Abstract

Old world monkey TRIM5α is a host factor that restricts human immunodeficiency virus type-1 (HIV-1) infection. Previously, we reported that rhesus macaque TRIM5α (RhTRIM5α) restricts HIV-1 production by inducing degradation of precursor Gag. Since suppressor of cytokine signaling 1 (SOCS1) is known to enhance HIV-1 production by rescuing Gag from lysosomal degradation, we examined if SOCS1 is involved in RhTRIM5α-mediated late restriction. Over-expression of SOCS1 restored HIV-1 production in the presence of RhTRIM5α to a level comparable to that in the absence of RhTRIM5α in terms of titer and viral protein expression. Co-immunoprecipitation studies revealed that SOCS1 physically interacted with RhTRIM5α. Over-expression of SOCS1 affected RhTRIM5α expression in a dose-dependent manner, which was not reversed by proteasome inhibitors. In addition, SOCS1 and RhTRIM5α were detected in virus-like particles. These results suggest that SOCS1 alleviates RhTRIM5α-mediated regulation in the late phase of HIV-1 life cycle probably due to the destabilization of RhTRIM5α.

Highlights

Old world monkey TRIM5a was originally identified as an intrinsic immune agent that blocks human immunodeficiency virus type-1 (HIV-1) infection immediately after viral entry [1]
To determine if suppressor of cytokine signaling 1 (SOCS1) is functionally involved in RhTRIM5amediated late restriction, we examined the effect of SOCS1 overexpression on RhTRIM5a-mediated inhibition of HIV-1 production, where the level of exogenously expressed Rhtrim5a mRNA was approximately 200-fold higher than that of endogenous trim5a mRNA in HEK293T cells
SOCS1 reproducibly reduced the expression level of RhTRIM5a (Figure 1, C and D), but did not affect the mRNA level of Rhtrim5a (Figure 1E). These results indicate that over-expression of SOCS1 reverses RhTRIM5a-mediated late restriction

Summary

Introduction

Old world monkey TRIM5a was originally identified as an intrinsic immune agent that blocks human immunodeficiency virus type-1 (HIV-1) infection immediately after viral entry [1]. TRIM5a carries RING, B-box, coiled-coil (RBCC) and B30.2/ SPRY domains. In the post-entry restriction, RhTRIM5a recognizes incoming viral cores, but not the capsid protein as a monomer, through the B30.2 domain. The B30.2 domain determines the antiviral spectrum and magnitude of post-entry restriction. The B-box and the coiled-coil domains are required to form homo/hetro-multimer [2,3,4] and the B30.2 domains of multimerized TRIM5a stick in the grooves on the surface of incoming viral cores [5,6]. After recognizing the structured core, RhTRIM5a induces aberrant disassembly of core, resulting in the disruption of reverse-transcription of viral genomic RNA [1]

Methods

Results

Conclusion