Abstract
Viroporins like influenza A virus M2, hepatitis C virus p7, HIV-1 Vpu and picornavirus 2B associate with host membranes, and create hydrophilic corridors, which are critical for viral entry, replication and egress. The 6K proteins from alphaviruses are conjectured to be viroporins, essential during egress of progeny viruses from host membranes, although the analogue in Chikungunya Virus (CHIKV) remains relatively uncharacterized. Using a combination of electrophysiology, confocal and electron microscopy, and molecular dynamics simulations we show for the first time that CHIKV 6K is an ion channel forming protein that primarily associates with endoplasmic reticulum (ER) membranes. The ion channel activity of 6K can be inhibited by amantadine, an antiviral developed against the M2 protein of Influenza A virus; and CHIKV infection of cultured cells can be effectively inhibited in presence of this drug. Our study provides crucial mechanistic insights into the functionality of 6K during CHIKV-host interaction and suggests that 6K is a potential therapeutic drug target, with amantadine and its derivatives being strong candidates for further development.
Highlights
Chikungunya fever is a severe and debilitating illness caused by the mosquito-borne arbovirus, Chikungunya Virus (CHIKV) [1,2,3,4]
Chikungunya fever is a severe crippling illness caused by the arthropod-borne virus CHIKV
The existing treatment against CHIKV is primarily symptomatic, and it is imperative that specific therapeutics be devised
Summary
Chikungunya fever is a severe and debilitating illness caused by the mosquito-borne arbovirus, Chikungunya Virus (CHIKV) [1,2,3,4]. The roles of capsid and envelope proteins in the life cycle of CHIKV are fairly well studied [9,10,11,12,13,14], reports pertaining to the direct functional characterization of 6K are rare, making it the least understood amongst all CHIKV structural proteins. One contributing factor for the lack of direct biochemical characterization of CHIKV 6K is its extreme intrinsic hydrophobicity, as well as cytotoxicity [7, 16], which makes the production of sufficient quantity of functionally active, recombinant protein fairly challenging. The molecular details of membrane association by 6K and the exact role of this activity in promoting virus budding remains unknown
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