An Engineered Microvirin Variant with Identical Structural Domains Potently Inhibits Human Immunodeficiency Virus and Hepatitis C Virus Cellular Entry.

Microvirin (MVN) is one of the human immunodeficiency virus (HIV-1) entry inhibitor lectins, which consists of two structural domains sharing 35% sequence identity and contrary to many other antiviral lectins, it exists as a monomer. In this study, we engineered an MVN variant, LUMS1, consisting of two domains with 100% sequence identity, thereby reducing the chemical heterogeneity, which is a major factor in eliciting immunogenicity. We determined carbohydrate binding of LUMS1 through NMR chemical shift perturbation and tested its anti-HIV activity in single-round infectivity assay and its anti-hepatitis C virus (HCV) activity in three different assays including HCVcc, HCVpp, and replicon assays. We further investigated the effect of LUMS1 on the activation of T helper (Th) and B cells through flow cytometry. LUMS1 showed binding to (1-2)mannobiose, the minimum glycan epitope of MVN, potently inhibited HIV-1 and HCV with EC50 of 37.2 and 45.3 nM, respectively, and showed negligible cytotoxicity with CC50 > 10 µM against PBMCs, Huh-7.5 and HepG2 cells, and 4.9 µM against TZM-bl cells. LUMS1 did not activate Th cells, and its stimulatory effect on B cells was markedly less as compared to MVN. Together, with these effects, LUMS1 represents a potential candidate for the development of antiviral therapies.

Potential targets for therapeutic intervention and structure based vaccine design against Zika virus.

Continuously increasing number of reports of Zika virus (ZIKV) infections and associated severe clinical manifestations, including autoimmune abnormalities and neurological disorders such as neonatal microcephaly and Guillain-Barré syndrome have created alarming situation in various countries. To date, no specific antiviral therapy or vaccine is available against ZIKV. This review provides a comprehensive insight into the potential therapeutic targets and describes viral epitopes of broadly neutralizing antibodies (bNAbs) in vaccine design perspective. Interactions between ZIKV envelope glycoprotein E and cellular receptors mediate the viral fusion and entry to the target cell. Blocking these interactions by targeting cellular receptors or viral structural proteins mediating these interactions or viral surface glycans can inhibit viral entry to the cell. Similarly, different non-structural proteins of ZIKV and un-translated regions (UTRs) of its RNA play essential roles in viral replication cycle and potentiate for therapeutic interventions. Structure based vaccine design requires identity and structural description of the epitopes of bNAbs. We have described different conserved bNAb epitopes present in the ZIKV envelope as potential targets for structure based vaccine design. This review also highlights successes, unanswered questions and future perspectives in relation to therapeutic and vaccine development against ZIKV.