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The first two steps in a viral life cycle involve attachment and entry. The range of host and tissue tropism is directly dependent on the first two steps listed above. It has been determined that there exists a great tissue tropism for dengue virus due to the possible presence of several cellular receptors. The viral receptor that has been identified for primary dengue virus infection is the E glycoprotein. This protein plays a critical role in controlling infection as well as tropism. Controversial theories exist however on the cellular receptor for attachment of dengue virus. Since dengue virus has been shown to replicate successfully in a wide variety of cell cultures obtained from mammalian and arthropod tissues, it may be possible that there may exist different receptors based on the type of host cell infected. Two glycoproteins have been reported as receptors for dengue - 4 infections. Also, two tubulin like proteins were identified as receptors for dengue virus 2 infections. Furthermore, a laminin - binding protein was established to be a common receptor for dengue - 3 and dengue - 4 viruses. Several different proteins receptors have been identified for different types of mammalian cells such as monocytes, macrophages, dendritic cells, B and T lymphocytes, endothelial cells, and bone marrow. These receptors may include heat shock proteins, laminin receptor, mannose receptor, CD - 14 associated protein, and DC - SIGN (1). Some researchers have shown that heparin sulfate was involved in the attachment of dengue virus cells. This receptor is commonly present on cells and serves as an initial receptor for many pathogens. The heparin sulfate receptor is specific to the highly sulfated form of the receptor. With the compilation of all of the above data is has been hypothesized that dengue E glycoprotein reacts with two possible targets on the cell (2). The first receptor may be the ubiquitous, low affinity heparan sulfate or DC - SIGN receptors that help accumulate the viral particles. The second receptor would then be a higher affinity one that would help with the physical entry of the viral particle. Variations are present in the E - glycoprotein based on the serotype of the virus and this variation will also influence viral interaction with the cells that get infected (1).
There are four well defined routes of entry that dengue virus may use. These include phagocytosis, macropinocytosis, clathrin - mediated endocytosis, and caveolae - mediated endocytosis. Some of the not so well characterized methods of entry include lipid raft - mediated endocytosis dependent on dynamin, lipid raft - mediated pathway independent of dynamin, and nonclathirin noncaveolar - mediated pathway which is independent of lipid rafts. According to some early studies the route of entry was primarily fusion at physiological pH, but now it has been determined that the route of entry for infection is receptor - mediated endocytosis at low pH. Membrane fusion occurs in endosomal compartments and the low pH conditions of these endosomes cause the viral E - glycoprotein to undergo a conformational change. This exposes the fusion domains that were previously hidden and initiates the membrane fusion process which releases viral RNA into the cytoplasm. Another group of researchers have recently demonstrated that dengue virus 2 enters via the clathirin dependent endocytosis route in mosquitoes as well as HeLa cells. Another route of entry that was shown for mosquitoes was independent of lipid raft integrity Thus a variety of results were obtained for routes of entry for dengue virus which prompts that dengue virus may employ several different routes of entry (1).
Once endocytosis has occurred and the virus has entered the cell, uncoating occurs via fusion of the envelope to the endosomal membrane. As discussed above, the low pH of the endosome causes a conformational change in the E glycoprotein which causes the exposure of the fusion domain that controls the fusion of the viral envelope. Dengue virus RNA is positive stranded that is structured like cellular mRNA. It possesses a 5' guanosine cap structure, a 5'untranslated region (UTR), one open reading frame, and a 3' UTR. The anomaly is that it lacks a polyadenylated tail. Due to the lack of Poly A tail dengue cannot use the same machinery that cellular mRNA uses. Therefore, dengue uses strategies such as the virus undergoes translation when cellular translation has been inhibited due to a coinfection with another virus, or under conditions with high osmolarity, or due to the repression of important initiation factors. Adaptation to the host may be the reason that dengue virus obtained this ability to translate under a variety of different conditions. Cellular tropism of the virus can be determined by the efficacy of the initial translation. It was demonstrated by a study conducted on different strains of dengue virus that the 3' UTR may be involved in regulation of translation. This region in partnership with the 5'UTR has been shown to possess properties that are similar to the poly A tail in promoting translation. After the preparation of translational machinery, the initial codon has to be spotted by the small ribosomal unit in order to start elongation. A hair pin structure downstream of the dengue virus - 2 start codon has been shown to help with enhancement of translation based upon its stability (3).
Dengue virus utilizes the same positive strand for both translation and replication. These two processes occur at different times. After the translation of the initial strand, the viral particle produces vRNA. This involves a negative strand RNA that can be used in the future for the production of more positive strands. Even though this is not well understood, it has been shown that the positive strand DNA is produced in excess by the virus. The 3'UTR discussed above that helped regulate translation also plays a role in the regulation of vRNA synthesis (3).
The synthesized RNA is packaged into a capsid by the C protein. Inside the lumen of the ER the prM and the E protein orient in an appropriate position. Then the prM and the E proteins associate with each other to form a curved surface structure. Since there no interactions spotted with C and prM, it may be assumed that is process is random. The assembled viral particle shows 60 spike projections that have formed by the heterodimeric associations between prM and E. This immature particle normally forms in the endoplasmic reticulum and maturation takes place as the viral particle goes through the secretory pathway. The low pH conditions of the trans- golgi network cause a dissociation between the prM and E protein and the fusion protein E is capped by the prM. This leads to the formation of dimers that tend to lay flat on the surface of the viral particle. The formation of this structure is what enables the furin (a cellular endoprotease) to cleave off the prM cap. Furin also caused the breaking apart of prM to for membrane associated peptides M and pr. These peptides have been shown to serve as chaperones for the E protein while it's travelling through the secretory pathway. They prevent any conformational change in the E protein that could lead to membrane fusion. Once the pr peptide dissociates, mature viral particle formation occurs. Mature particles then egress through the cell through exocytosis (4).