Chemotherapeutic approaches to the control of viral infections have been less successful than those against bacterial infections because of the need of viruses to replicate in host cells and the attendant difficulty in selectively targeting the virus without damaging the host. To date, virtually all strategies for the development of antiviral drugs have focused on unique properties of the viral replicative cycle or of viral proteins that can be selectively targeted (1
). These drugs include nucleoside analogues and inhibitors of viral polymerase, protease, and fusion proteins. Most of the antiviral drugs currently in use are directed against persistently infecting viruses, such as HIV, where therapy is expected to continue for a long duration. Acute viral infections, however, may need only a short period of drug treatment to shift the balance between overwhelming and lethal virus load on the one hand and an effective and protective immune response on the other. Because viruses are dependent on host-cell functions for their replication, we questioned whether a transient and well-tolerated interference of the normal functions of the cell types in which the virus replicates may retard viral replication and/or spread and spare the host from morbidity or mortality.
Smallpox was due to infection with variola major or variola minor of the orthopox genus, which belong to the poxvirus family of large double-stranded DNA viruses replicating in the cytoplasm of infected cells (4
). Cessation of vaccination efforts more than 2 decades ago has resulted in susceptibility of a large segment of the population to this pathogen (5
). This vulnerability requires additional methods to rapidly contain any future outbreak of infections from this group of viruses.
EGF-like growth factors are carried by poxviruses to facilitate viral pathogenesis. Prominent skin manifestations elicited by a number of these viruses are probably linked to this gene product (4
). Prior gene deletion studies showed that vaccinia growth factor (VGF) of the variola-related orthopox vaccinia virus (VV) contributes to virulence following intracranial inoculation of mice and intradermal inoculation of rabbits (6
). Likewise, inactivation of myxoma growth factor in the distantly related leporipoxvirus diminishes viral-induced proliferation of epithelial cell layers in conjunctival and respiratory tracts (7
). Since smallpox growth factor (SPGF) uses ErbB-1 to stimulate host cells (8
), thereby aiding viral replication, we reasoned that if the viral factor’s stimulatory activity was blocked, then viral growth might be curtailed.
The ErbB 1–4 molecules are members of the receptor tyrosine kinase superfamily and share common structural features, including an extracellular ligand–binding domain, a transmembrane segment, and an intracellular protein tyrosine kinase (PTK) domain (ref. 9
and references therein). These receptors mediate physiologic growth factor signaling by EGF, TGF-α, epiregulin, amphiregulin, and neuregulin, among other growth factors. Although related, there are evident differences in the substrate specificity, signaling properties, and physiology of these receptors. ErbB-2 has no known extracellular ligand, and tyrosine kinase activity is absent in ErbB-3. In addition, heterodimerization and homodimerization of ErbB members contribute to signaling complexity, forming a multilayered network of functional interaction in higher eukaryotes, unlike the single, primordial ErbB homologue found in Caenorhabditis elegans
). Since more than 60% of human tumors contain ErbB abnormalities, including receptor overexpression via gene amplification and/or rearrangement and ErbB receptor–specific ligand aberrations, which contribute to the malignant phenotype (9
), approaches have been developed to block ErbB signal transduction. Clinical inhibitors of ErbB receptor tyrosine kinase pathways are being extensively investigated as anticancer agents in many human malignancies (10
The present study was conducted to determine whether such inhibitors might block orthopox infection and the effects of the EGF-like pathogenic factors in vitro and in vivo. We show here that chemical interference with the signal transduction mediated by ErbB-1 can lead to the control of variola virus in vitro and of VV in vivo. Thus, targeting of a host cell signal transduction function needed for viral replication can be used as a new approach to antiviral chemotherapy.