Insights into Dengue Virus Genome Replication

Abstract

Since many antiviral drugs are designed to interfere with viral genome replication, understanding this step in the viral replicative cycle has gained importance in recent years. Replication for many RNA viruses occurs in cellular compartments mainly originated from the production and reorganization of virus-induced membranes. Dengue virus translates, replicates and assembles new viral particles within virus-induced membranes from endoplasmic reticulum. In these compartments, all of the components required for replication are recruited, making the process efficient. In addition, membranes protect replication complexes from RNAases and proteases, and ultimately make them less visible to cellular defense sensors. Although several aspects in dengue virus replication are known, many others are yet to be understood. This article aims to summarize the advances in the understanding of dengue virus genome replication, highlighting the cis as well as trans elements that may have key roles in this process. Keywords n dengue virus n endoplasmic reticulum n nonstructural proteins n replicative complex n RNA-protein interactions n RNA-RNA interactions n transacting factors n viral proteins n viral replicase n viral RNA

Overlapping Local and Long-Range RNA-RNA Interactions Modulate Dengue Virus Genome Cyclization and Replication

“…The DENV genome is a plus-stranded RNA molecule that contains a single open reading frame flanked by highly structured 5= and 3= untranslated regions (UTRs) (1)(2)(3). RNA elements located within these regions are responsible for translation initiation and genome replication (4)(5)(6)(7). The 5= UTR is about 100 nucleotides (nt) long and includes three different elements: (i) stem-loop A (SLA), which is the promoter for viral polymerase binding and activation (8)(9)(10); (ii) stem-loop B (SLB), which contains a sequence known as 5= upstream of the AUG region (5= UAR) that is complementary to a sequence present at the 3= UTR (3= UAR) and mediates longrange RNA-RNA interactions between the ends of the genome (11); and (iii) a spacer sequence between SLA and SLB rich in U's, which functions as an enhancer of viral replication (10).…”

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

“…It encodes 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), which, together with the 3 structural proteins, are all derived from the proteolytic processing of a single polyprotein (4). Replication of DENV occurs in close association with rough endoplasmic reticulum (RER) and is presumed to require the assistance of cellular proteins, both for replication/translation of the genome and for the correct folding of viral proteins (5,6). Nucleocapsids acquire their envelope by budding into the RER.…”

Dengue Vaccine Development: Strategies and Challenges

“…A strategy to avoid detection is the formation of isolated intracellular regions. DENV generates convoluted membranes, around which host and viral factors that are necessary for viral replication and translation localize (2). This region, within the cytosol, is remote, creating a microenvironment that is difficult for pattern recognition systems to detect.…”

“…The primary target of DENV is the immature dendritic cell, and entry into host cells is facilitated by the binding of E protein to its cognate receptor, dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) (87). Once internalized, the virion is taken up into endocytic vesicles, where the low-pH environment induces fusion of the envelope and the endosomal membranes, leading to the release of the infectious viral RNA into the cytoplasm, where viral replication and translation occur (2,3,67).…”