Abstract
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 α(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.
Highlights
Human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV) infections continue to be a healthcare challenge globally, accounting for an enormous disease burden [1,2,3]
A characteristic feature of HIV-1 entry inhibitor lectins is multivalent recognition through more than one carbohydrate-binding site to attain high avidity of interaction required for potent antiviral activity
The removal of the four residues corresponding to a long flexible loop could further minimize chemical heterogeneity and reduce the protein size
Summary
Human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV) infections continue to be a healthcare challenge globally, accounting for an enormous disease burden [1,2,3]. An effective vaccine against these viruses remains to be developed. Advancement in the development of anti-viral regimens has improved the situation, in controlling HCV infections [4,5]. The outcome of antiviral therapies could be limited by several factors, including the possible emergence of drug-resistant viral variants. This scenario, signifies the continuous efforts towards the development of new anti-viral therapies or preventive measures. The common feature between HIV-1 and HCV is the presence of highly glycosylated outer envelope—the envelope glycoprotein 120 (gp120) of HIV-1 and E2 of HCV exhibits over 20 and 11
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