Keith J. Halford
Amy T. Pierce
William P. Halford
2005
<p><span>Several studies suggest that the innate interferons (IFNs), IFN-</span><span id="mmlsi72" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si72.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=59a5b4e51667314cc0314b9f6293717a">α</span></span><span> and IFN-</span><span id="mmlsi73" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si73.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=8356c234c0242fe808632adce9d89766">β</span></span><span>, can act in concert with IFN-</span><span id="mmlsi74" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si74.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=a45eb6d9b4062347907d10d8968b516d">γ</span></span><span>to synergistically inhibit the replication of cytomegalovirus and herpes simplex virus type 1 (HSV-1). The significance of this observation is not yet agreed upon in large part because the nature and magnitude of the interaction between IFN-</span><span id="mmlsi75" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si75.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=ea2c937d69007a9a05b8dfb230f317c3">α/β</span></span><span> and IFN-</span><span id="mmlsi76" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si76.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=911044e95785060ad770ad9d0a4eddc3">γ</span></span><span> is not well defined. In the current study, we resolve this issue by demonstrating three points. First, the hyperbolic tangent function, tanh (</span><i>x </i><span>), can be used to describe the individual effects of IFN-</span><span id="mmlsi77" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si77.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=d5bddaa93b7165e922be18040e0307ac">β</span></span><span> or IFN-</span><span id="mmlsi78" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si78.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=29e3d4d655370c831a1e11a8fd5ec461">γ</span></span><span> on HSV-1 replication over a 320,000-fold range of IFN concentration. Second, pharmacological methods prove that IFN-</span><span id="mmlsi79" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si79.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=a6551744ad83f208aff62aa4470cb926">β</span></span><span> and IFN-</span><span id="mmlsi80" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si80.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=3972c8fe88951a5ae8414a583df23f4f">γ</span></span><span> interact in a greater-than-additive manner to inhibit HSV-1 replication. Finally, the potency with which combinations of IFN-</span><span id="mmlsi81" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si81.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=aa46d4c5cf215e1c6bbab543c0286ded">β</span></span><span> and IFN-</span><span id="mmlsi82" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si82.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=f3202d0b3b85c1c01c1e780abb47912a">γ</span></span><span> inhibit HSV-1 replication is accurately predicted by multiplying the individual inhibitory effects of each cytokine. Thus, IFN-</span><span id="mmlsi83" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si83.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=e784c7f222c6a45bf0c0622fb762ac6c">β</span></span><span> and IFN-</span><span id="mmlsi84" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si84.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=8b4aa0ad1e351d96e0568b8861997d28">γ</span></span><span> interact in a multiplicative manner. We infer that a primary antiviral function of IFN-</span><span id="mmlsi85" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si85.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=c0e4015a569a996aad96052f0f7a5217">γ</span></span><span> lies in its capacity to multiply the potency with which IFN-</span><span id="mmlsi86" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si86.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=8f4a70a02d48c0d9c66843eddac6090d">α/β</span></span><span> restricts HSV-1 replication in vivo. This hypothesis has important ramifications for understanding how T lymphocyte-secreted cytokines such as IFN-</span><span id="mmlsi87" class="mathmlsrc"><span class="formulatext stixSupport mathImg" title="Click to view the MathML source" data-mathurl="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S0022519304006058&_mathId=si87.gif&_user=111111111&_pii=S0022519304006058&_rdoc=1&_issn=00225193&md5=97ea36335b1ba50de5cf9247fee36420">γ</span></span><span> can force herpesviruses into a latent state without destroying the neurons or leukocytes that continue to harbor these viral infections for the lifetime of the host.</span></p>
application/pdf
10.1016/j.jtbi.2004.12.007
en
Elsevier
Mathematical analysis demonstrates that interferons-β and -γ Interact in a multiplicative manner to disrupt herpes simplex virus replication
article