Operating under a Gag order: a block against incoming virus by the Fv1 gene.

Stoye's findings now explain how Fv1 probably works. The gene was isolated by positional cloning. Beginning with a marker nearby on chromosome 4, successively smaller YACs and cosmids were recovered, with the gene being scored by direct bioassay: candidate DNAs were tested after transfection for their ability to render the cells resistant to subsequent challenge with genetically marked virus. Astonishingly, the activity localized to a small, intronless ORF with sequence similarity to the HERV-L family of human endogenous retroviruses (60% identity over 1.3 kb; Cordonnier et al. 1995xCordonnier, A, Casella, J.-F, and Heidmann, T. J. Virol. 1995; 69: 5890–5897PubMedSee all ReferencesCordonnier et al. 1995). Similar elements are widespread in mammalian genomes and are transmitted in trans by helper retroviruses as defective genomes. Based on its position in the element, the Fv1 gene is apparently a gag gene, but a very peculiar one, having only very little similarity to known gags. The Fv1n allele differs from Fv1b by several point mutations and a different C-terminal sequence, presumably accounting for the specific block against B- and N-tropic Gags. The locus is expressed at excruciatingly low levels. What is appealing about the result is that Gag proteins are known to bind tightly to each other, and to do so via complex interaction domains. The simple model for Fv1 action is that the HERV-L Gag can bind to the Gag of incoming preintegration complexes and block its normal movement into the nucleus for DNA integration, or its function once there. The Fv1 version of this HERV-L Gag must be extraordinary one - a dominant negative mutant - since most Gags do not mediate a superinfection barrier.The identification of Fv1 as a gag has several nice features. First, the result gives us a more concrete picture of the resistance, accounting for the specificity of the alleles for subtly different Gag proteins, the aberrant titration behavior of virus on nonpermissive cells, and the abrogation of resistance by inactivated virions. It accounts for the behavior of mixed particles, which would carry CAs able to bind either the Fv1n or Fv1b allelic HERV-L Gag proteins. Second, the finding means that a dominant negative version of a Gag protein that is resident at very low levels in a cell can exert strong resistance against incoming virus. It may turn out that one or a very few Fv1 molecules can inactivate one preintegration complex (containing, at least upon cell entry, about 1500 CA molecules). This may herald further good news in the AIDS field, especially to those hoping to use dominant negative versions of viral genes to similarly render cells resistant to virus. Third, importantly, the result suggests a reason for the mouse to retain such an endogenous retroviral element as a helpful gene during evolution. Mice carrying Fv1 would show a selective advantage over Fv1 null littermates in resisting disease; indeed, active Fv1 alleles are found only in mice carrying many endogenous MuLVs, and not in related species with fewer endogenous proviruses. The finding suggests that the repertoire of defective retroviral DNAs carried in the genome has sometimes served purposes useful to the host. And, finally, the result suggests a clear plan for structural biologists to pursue in the future. The recent progress in the determination of the structure of a retroviral CA (Gitti et al. 1996xGitti, R.K, Lee, B.M, Walker, J, Summers, M.F, Yoo, S, and Sundquist, W.I. Science. 1996; 273: 231–235Crossref | PubMedSee all ReferencesGitti et al. 1996) will quickly permit tests of various models for Gag–HERV-L interactions. Based on these structures, there are indications that the Fv1 tropism region of CA may indeed be exposed to the outside of the virion core, and a direct biochemical demonstration of the interaction should be imminent.The identity of the Fv1 gene as a gag gene is a clear example of irony. The resistance gene that was sought for twenty years was right in front of us all the time: it was a portion of the very virus family being resisted. Indeed, the gene was probably once delivered into the mouse germ line by a replication-competent helper virus. The only sad aspect of the story is that two of the original founders of the field—Wally Rowe and Frank Lilly (who passed away this past year, and to whom Stoye's paper is dedicated)—did not live to see this denouement. As virologists they would have loved it.