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      Regulation of HCV infection by Cellular Retinoic Acid Binding Proteins through the modulation of lipid droplet abundance

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          Abstract

          Retinoid (vitamin A) is an essential diet constituent that governs a broad range of biological processes. Its biologically active metabolite, all-trans retinoic acid (ATRA), exhibits a potent antiviral property by enhancing both innate and adaptive antiviral immunity against a variety of viral pathogens such as, but not limited to, HIV, RSV, HSV, and measles. Even though the hepatocyte is highly enriched with retinoid and its metabolite, ATRA, it supports the establishment of efficient hepatitis C virus (HCV) replication. Here, we demonstrate the hepatocyte-specific cell-intrinsic mechanism by which ATRA exerts either proviral or antiviral effect, depending on how it engages cellular retinoic acid binding proteins (CRABPs). We found that the engagement of CRABP1 by ATRA potently supported viral infection by promoting the accumulation of lipid droplets (LDs), which robustly enhanced the formation of a replication complex on LD-associated ER membrane. In contrast, ATRA binding to CRABP2 potently inhibited HCV via suppression of LD accumulation. However, this antiviral effect of CRABP2 was abrogated due to the functional and quantitative predominance of CRABP1 in the hepatocytes. In summary, our study demonstrated that CRABPs serve as an on-off switch that modulates the efficiency of HCV lifecycle and elucidated how HCV evades the antiviral properties of ATRA via the exploitation of CRABP1 functionality.

          IMPORTANCE ATRA, a biologically active metabolite of vitamin A, exerts pleiotropic biological effects including the activation of both innate and adaptive immunity, thereby serving as a potent antimicrobial compound against numerous viral pathogens. Despite the enrichment of hepatocytes with vitamin A, HCV still establishes an efficient viral lifecycle. Here, we discovered that the hepatocellular response to ATRA creates either a proviral or an antiviral environment depending on its engagement with CRABP1 or 2 respectively. CRABP1 supports the robust replication of HCV while CRABP2 potently inhibited the efficiency of viral replication. Our biochemical, genetic, and microscopic analyses reveal that the pro- and antiviral effects of CRABPs are mediated by modulation of the LD abundance where HCV establishes the platform for viral replication and assembly on the LD-associated ER membrane. This study uncovered a cell-intrinsic mechanism by which HCV exploits the proviral function of CRABP1 to establish an efficient viral lifecycle.

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          Author and article information

          Journal
          Journal of Virology
          J Virol
          American Society for Microbiology
          0022-538X
          1098-5514
          February 06 2019
          Article
          10.1128/JVI.02302-18
          6450116
          30728260
          8f2a7866-4b92-48f3-af53-ffbc1553f72b
          © 2019
          History

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