Dengue virus entry and trafficking: perspectives as antiviral target for prevention and therapy

Abstract

Dengue virus (DENV) is the etiological agent of the most important human viral infection transmitted by mosquitoes in the world. In spite of the serious health threat that dengue represents, at present there are no vaccine or antiviral agents available and treatment of patients consists of supportive therapy. This review will focus on the process of DENV entry into the host cell as a potential target for antiviral therapy. The recent advances in the knowledge of viral and cellular molecules and mechanisms involved in binding, internalization and trafficking of DENV into the host cell until virion uncoating are discussed, together with an overview of the strategies and compounds evaluated for development of antiviral agents targeted to DENV entry. KeywordsDengue is currently the most widespread arbovirosis in the world, with a particularly high prevalence in diverse tropical and subtropical regions of America and Asia [1]. The WHO estimates an occurrence of 50-100 million annual infections, but more recent modelling evaluations increased the number of new possible infections to 390 million per year [2]. There are four serotypes of dengue viruses (DENV), designated DENV-1 to DENV-4, that cocirculate and are transmitted to humans by the bites of the mosquitoes Aedes aegypti and Aedes albopictus. Precisely, the failure in the programs for control of the mosquito vector is one of the reasons for the explosive re-emergence and global spread of dengue in the last few decades in >100 countries, resulting in a serious public health challenge.All serotypes can produce either an inapparent infection or a wide spectrum of clinical outcomes ranging from a mild febrile illness known as dengue fever (DF) to the more severe and life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [3]. The initial infection with one DENV serotype leads to lifelong protection against homologous reinfection, but only brief and partial protection against infection with other serotypes. In fact, the secondary infection with a heterologous serotype is considered a risk factor for developing DHF and DSS. These severe clinical manifestations have been associated to the phenomenon known as antibody-dependent enhancement (ADE) [3]. In this process, the antibodies elicited by the primary infection bind to the heterotypic virus without neutralization of viral infectivity, and these immune complexes are opsonized into Fc-receptor positive cells leading to an increase in DENV replication and pathogenesis [4,5].DENV is a member of the genus Flavivirus in the family Flaviviridae. The virion is a small spherical particle, 40-50 nm in diameter, containing a single-stranded positive sense RNA included in an inner nucleocapsid and surrounded by a lipid envelope. The virus genome codes for a single polyprotein that is cleaved into three structural proteins (the capsid protein C,

A Computational Approach on Understanding Structural Interactions of Envelope Protein of Dengue Virus Bound With Squalene, a Prototype Anti-Viral Compound

“…Dengue is one of the NTDs and the disease is originated from the dengue viruses belong to Flavivirus, which is the genus of the family Flaviviridae. The dengue viruses cause Encephalitis in a human being and the people with encephalitis suffer from fever, seizures, severe headache, photophobia, cough and drowsiness [4]. There are no specific anti-viral drugs and vaccination to treat the dengue disease to date, though drugs such as ribavirin, acyclovir and EICAR are being used to treat the infections at the present juncture [5].…”

Dengue-3 Virus Entry into Vero Cells: Role of Clathrin-Mediated Endocytosis in the Outcome of Infection

“…In the past few years, several strategies targeted to different stages of DENV life cycle were intended for antiviral development [ 4 , 5 ]. In particular, virus entry has become an attractive alternative for therapeutic intervention against viruses, since it represents a barrier to block the beginning of infection and it is determinant of viral tropism and pathogenesis [ 6 – 9 ].…”

Antibody-Dependent Enhancement of Viral Infections

“…Cells of the mononuclear phagocyte lineage, like monocytes, macrophages, and dendritic cells, are the main targets for DENV infection in humans. Attachment of DENV E protein (EDIII) to putative cell surface receptors such as heparan sulfate, C-type lectins, heat shock protein 70/90, and phosphatidylserine receptors constitutes the first step of viral infection (Castilla et al 2015;Cruz-Oliveira et al 2015). This is followed by penetration of the host cell by receptor-dependent, clathrin-and dynamin-mediated endocytic pathway.…”