Poxvirus interleukin-4 expression overcomes inherent resistance and vaccine-induced immunity: pathogenesis, prophylaxis, and antiviral therapy.
In 2001, Jackson et al. reported that murine IL-4 expression by a recombinant ectromelia virus caused enhanced morbidity and lethality in resistant C57BL/6 mice as well as overcame protective immune memory responses. To achieve a more thorough understanding of this phenomenon and to assess a variety of countermeasures, we constructed a series of ECTV recombinants encoding murine IL-4 under the control of promoters of different strengths and temporal regulation. We showed that the ECTV-IL-4 recombinant expressing the highest level of IL-4 was uniformly lethal for C57BL/6 mice even when previously immunized. The lethality of the ECTV-IL-4 recombinants resulted from virus-expressed IL-4 signaling through the IL-4 receptor but was not due to IL-4 toxicity. A number of treatment approaches were evaluated against the most virulent IL-4 encoding virus. The most efficacious therapy was a combination of two antiviral drugs (CMX001(®) and ST-246(®)) that have different mechanisms of action.
Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, CA 92109, USA.
Nanhai
N
Chen
Clifford J
CJ
Bellone
Jill
J
Schriewer
Gelita
G
Owens
Torgny
T
Fredrickson
Scott
S
Parker
R Mark L
RM
Buller
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D003596:Cytosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004481:Ectromelia virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D004482:Ectromelia, Infectious / Q000188:drug therapy / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D054833:Isoindoles / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D010797:Phthalimides
D000998:Antiviral Agents; D001549:Benzamides; D003596:Cytosine; D015847:Interleukin-4; D054833:Isoindoles; D063065:Organophosphonates; D011994:Recombinant Proteins; C525733:brincidofovir; C505045:tecovirimat; D010797:Phthalimides