A cure for influenzaI know all my regular readers1 are expecting me to talk about the bombshell announcements that NK cells have memory, but I’ll put that off for a bit and instead quickly note a very cool advance on a story I’ve mentioned a few times before.

Interferons are among the most critical early warning and protective cytokines, and they’re so effective that just about any successful virus of vertebrates has strong defenses against them. Without those defenses, the virus is essentially dead. For example, in some cases the the virus’s interferon blocker only works in one species, and that limits the virus to infecting that species only; if you get rid of the interferon response that the virus can’t deal with, then it’s perfectly capable of infecting other species.2 

Influenza viruses are no exception; they possess a gene (NS1) that protects them against the host interferons. (Some strains of influenza have especially effective NS1 functions, and it’s been suggested that those with the most effective interferon blockers are the most virulent pathogens — like the 1918 flu, or avian influenza). I’ve talked about NS1 before here.

When you eliminate NS1 from influenza, the virus is — as you’d expect — greatly weakened, and infection with these defective viruses cranks up interferon and thereby, in turn, cranks up the rest of the immune response. That gives you a highly attenuated, highly immunogenic virus, which is exactly what you want to use for a vaccine; and indeed, NS1-defective influenza viruses are apparently effective and safe vaccines.3 (I’ve previously mentioned a vaccinia virus vaccine technique that follows a similar approach, with similar results.)

So NS1 is clearly an extremely important molecule for influenza, and without it, the virus is basically harmless. What if you could block NS1 after an infection? Would it do the same thing — in other words, would an NS1-blocker be an antiviral treatment?

As it turns out: Yes, it would. Daniel Engel’s lab developed a group of compounds that inhibit influenza NS1. These things inhibit influenza growth in cells, and (although NS1 has functions other than blocking interferon) the effect was dependent on the interferon response. 4

A couple of viral immune evasion molecules have already been targeted for antiviral therapy — for example,  Luis Sigal  has shown that a poxvirus immune evasion molecule is a good vaccine target5 — but as far as I know this is the first antiviral compound that’s specifically been developed to inactivate an immune evasion molecule, and it offers the potential for a brand-new class of antivirals. Of course there are still huge barriers between these particular compounds and actual therapy in infected animals, but it’s encouraging that they work at all, and I’m interested in seeing what arises from it.

  1. Hi, Mom![]
  2. Wang F , Ma Y , Barrett JW , Gao X , Loh J , Barton E , Virgin HW , McFadden G (2004) Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat Immunol 5: 1266-1274[]
  3. Live Attenuated Influenza Viruses Containing NS1 Truncations as Vaccine Candidates against H5N1 Highly Pathogenic Avian Influenza. John Steel, Anice C. Lowen, Lindomar Pena, Matthew Angel, Alicia Solórzano, Randy Albrecht, Daniel R. Perez, Adolfo García-Sastre, and Peter Palese. Journal of Virology, February 2009, p. 1742-1753, Vol. 83, No. 4 doi:10.1128/JVI.01920-08 []
  4. D. Basu, M. P. Walkiewicz, M. Frieman, R. S. Baric, D. T. Auble, D. A. Engel (2008). Novel Influenza Virus NS1 Antagonists Block Replication and Restore Innate Immune Function Journal of Virology, 83 (4), 1881-1891 DOI: 10.1128/JVI.01805-08[]
  5. The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination. Xu RH, Cohen M, Tang Y, Lazear E, Whitbeck JC, Eisenberg RJ, Cohen GH, Sigal LJ. J Exp Med. 2008 Apr 14;205(4):981-92. doi:10.1084/jem.20071854 []