Advancements in Host-Based Interventions for Influenza Treatment (Hong Kong 2018-07-10)

[-] TrumpLyftAlles | 1 points | Sep 03 2020 01:12:32

Not covid-19 related (obviously). The article covers a number of possible treatments for influenza, including (obviously) ivermectin. I've seen a few warnings about the unhappy twofer we're facing, with flu season coming while the pandemic rages on. If ivermectin is effective against the flu, that's a twofer of a different color.

The proposition depends on ivermectin's mechanism of blocking importin-α/β1. It seems like there's lots of consensus that ivermectin does that, but Dog knows if it's really true.

vRNP = viral ribonucleoprotein
IAV = Influenza A virus

Nuclear import of vRNP complexes from the cytoplasm following fusion of the viral and the endosomal membrane is required for replication to take place (59). An early study suggested that vRNP complexes could be transported to the periphery of the nucleus (60), while recent studies report that vRNP complexes utilize the importin-α-importin-β1 (IMPα-IMPβ1) system for nuclear import (59, 61) and lacking of importin-α7, in an importin-α7 knockout mouse model were found to be resistant to IAV infection (62).

AFAICT (as far as I can tell) the above is a general statement about how viruses work. I'm guessing.

I lose the sense where "and lacking" starts. Anyone?

Ivermectin has long been clinically administered for the treatment of parasitosis (63), but has recently come to attention as a potential inhibitor of IMPα/β (64). Ivermectin inhibition of IMPα/β has shown to inhibit the replication of RNA viruses such as dengue virus and HIV-1 (64). Ivermectin was recently tested for the inhibition of IAV in vitro, with nuclear import of vRNP complex (of both wild-type and antiviral MxA escape mutant) efficiently inhibited (65). Given ivermectin’s longstanding record of clinical applications and FDA-approved status, repurposing of this drug for the treatment of IAV should be considered, especially while under threat of pandemic IAV outbreak.

[-] TrumpLyftAlles | 1 points | Sep 03 2020 01:27:21

If you're curious, this is the paper referenced by (65):

Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import

Abstract
To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic.

I think the "also an associated block in nuclear vRNP import" is what the (referencing) paper was referring to, and the thing being blocked is the importin-α/β1 transport mechanism.

Trying to find out what the MxA restriction is about, I came across this:

Background & Aims Non-cytolytic cure of HBV-infected hepatocytes by cytokines, including type I interferons (IFNs), is of importance for resolving acute and chronic infection. However, as IFNs stimulate hundreds of genes, those most relevant for HBV suppression remain largely unknown. Amongst them are the large myxovirus resistance (Mx) GTPases. Human MX1 (or MxA) is active against many RNA viruses, while MX2 (or MxB) was recently found to restrict HIV-1, HCV, and herpesviruses. Herein, we investigated the anti-HBV activity of MX2.

I gather that MxA is good when you're fighting viruses. I guess the "restriction factor MxA" means MxA restricts the virus.