IFN mimetic as a therapeutic for lethal vaccinia virus infection: possible effects on innate and adaptive immune responses.
We have developed small peptide mimetics of IFN-gamma that can bypass the poxvirus virulence factor B8R protein, which binds to intact IFN-gamma and prevents its interaction with receptor extracellular domain. Thus, these peptides inhibit vaccinia virus replication in cell culture where intact IFN-gamma is ineffective. We demonstrate here that the mouse IFN-gamma-mimetic peptide, IFN-gamma(95-132), protects C57BL/6 mice against overwhelming lethal vaccinia virus infection. The mimetic peptide was synthesized with an attached lipophilic group for penetration of cell plasma membrane. Injection of mimetic i.p. before and at the time of intranasal (10(6) PFU) or i.p. (10(7) PFU) challenge with virus resulted in complete protection at 200 microg of mimetic and 40-60% protection at 5 microg of mimetic. Initiation of treatment of mice with IFN-gamma mimetic up to 2 days postinfection resulted in complete protection against death, whereas initiation of treatment at 6 days postinfection resulted in 40% protection. Administration of mimetic by the oral route also completely protected mice against the intranasal route of a lethal dose of vaccinia virus challenge. In addition to its direct antiviral effect, the mimetic also possessed adjuvant effects in boosting humoral and cellular immunity to vaccinia virus. The combination of antiviral and adjuvant effects by the IFN mimetic probably plays a role in its potent anti-vaccinia virus properties. These results suggest an effective therapeutic against ongoing, lethal poxvirus infections that taps into innate and adaptive host defenses.
Ahmed
Chulbul M
CM
Department of Microbiology and Cell Science, University of Florida, Museum Road, Gainesville, FL 32611, USA. ahmed1@ufl.edu
Martin
James P
JP
Johnson
Howard M
HM
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D040761:Biomimetic Materials / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D007371:Interferon-gamma / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017471:Receptors, Interferon / Q000378:metabolism; D014615:Vaccinia / Q000188:drug therapy / Q000517:prevention & control*; D014616:Vaccinia virus / Q000187:drug effects*; D000096743:Interferon gamma Receptor
D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D010446:Peptide Fragments; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C520368:IFN-gamma(95-132) peptide; C079868:gamma interferon activation factor