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Host-based antipoxvirus therapeutic strategies: turning the tables
Anthony S. Fauci and Mark D. Challberg
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Address correspondence to: Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, NIH, Building 31, Room 7A03, 9000 Rockville Pike, Bethesda, Maryland 20892-2520, USA. Phone: (301) 496-2263; Fax: (301) 496-4409; E-mail: afauci@niaid.nih.gov.
Find articles by Fauci, A. in: JCI | PubMed | Google Scholar
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Address correspondence to: Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, NIH, Building 31, Room 7A03, 9000 Rockville Pike, Bethesda, Maryland 20892-2520, USA. Phone: (301) 496-2263; Fax: (301) 496-4409; E-mail: afauci@niaid.nih.gov.
Find articles by Challberg, M. in: JCI | PubMed | Google Scholar
Published February 1, 2005 - More info
J Clin Invest. 2005;115(2):231–233. https://doi.org/10.1172/JCI24270.
© 2005 The American Society for Clinical Investigation
Developing medical interventions against the threat of bioterrorism has been a part of the national biomedical research agenda at least since the days of the Cold War. However, the immediacy of such a threat was not fully appreciated until the events of the fall of 2001. The attacks on the World Trade Center and the Pentagon and the subsequent release of anthrax spores that infected 22 people and killed 5 transformed a remote possibility into somber reality (1).
Of special concern are category A agents and the need to develop countermeasures against these agents, which are known to cause fatal diseases such as anthrax, smallpox, plague, botulism, tularemia, and viral hemorrhagic fevers (2). The need for countermeasures against the Variola major virus, which causes smallpox, is especially acute because the virus is highly lethal and easily transmitted from person to person and because no effective treatments have yet been approved for use in humans. As a result of the successful global eradication of smallpox in 1977, routine vaccinations have been discontinued, and most people today have little or no immunity against the virus. Concerns about unaccounted-for stocks of smallpox virus surfaced after the fall of the Soviet Union, when it was revealed that massive quantities of the virus had been produced, further heightening the sense of urgency for the development of new therapies (2–4). An effective smallpox vaccine exists, and several new vaccine candidates are now being tested. Should a deliberate release of smallpox occur, however, it is important to have drug treatments readily accessible to protect against disease and to reduce any adverse effects of a live or attenuated smallpox vaccine. Currently, no such treatments are available, although cidofovir, a nucleoside analog that inhibits viral replication, is being tested clinically for treatment of some poxvirus infections (5, 6).
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CI-1033 prevents viral replication in vitro
Traditional antiviral drugs are generally directed against the proteins and functional pathways of the virus itself. For example, numerous therapies have been developed against HIV that interfere with viral reverse transcriptase, protease, and integrase as well as viral components involved in the binding and fusion of the virus to the target cell (7). However, many viruses evolve rapidly, particularly under selective pressures, and drug resistance almost invariably develops.
Because viruses typically rely upon cellular pathways to self-propagate, another antiviral approach would be to develop drugs that interfere with viral functions that are dependent on the functional machinery of the cell. Such an approach has been adopted by Yang et al., who report in this issue of the JCI (8) on a class of drugs originally developed as anticancer agents that show promise against orthopoxviruses and perhaps other viruses as well.
It has previously been shown that a growth factor (GF) encoded by the genomes of all orthopoxviruses (smallpox growth factor [SPGF] by variola virus, vaccinia growth factor [VGF] by vaccinia virus) binds to and activates the ErbB-1 kinase, a member of the epidermal GF receptor family of tyrosine kinases (9, 10). Because the poxvirus-encoded GFs are important for viral pathogenesis (11, 12), it seemed likely that inhibiting the cellular GF receptor might be a useful approach to controlling poxvirus infection. Yang et al. now demonstrate that inhibitors of cellular ErbB-1 do in fact disrupt important processes of the viral replication cycle and may represent an important new approach to antiviral chemotherapy (8).
This paper also provides new insight into the role of the poxvirus-encoded GFs in viral pathogenesis, suggesting that poxvirus GFs may play a direct role in virus replication. Previous studies have suggested that VGF acts on cells to stimulate metabolism, thereby increasing the number of cells capable of supporting efficient viral replication (11). Yang et al. (8) examined the effect of the ErbB inhibitor CI-1033 on the growth of variola and vaccinia virus — a smallpox-like virus — in infected monkey kidney cells in vitro. The drug had no effect on the overall yield of newly made virus in cell culture experiments in which all the cells in the culture were infected simultaneously, but it did have an effect on the appearance of plaques, which arise from the initial infection of a single cell and require local spread of the virus from the infected cell to surrounding uninfected cells. Two distinct forms of infectious virions are produced in poxvirus-infected cells: intracellular mature virus (IMV), which is released only following death and lysis of infected cells, and extracellular-enveloped virus (EEV), which is actively extruded from cells by interaction with actin tails (13) (Figure 1). The release of EEV from infected cells is thought to be the principal mechanism for rapid spread of the virus in the infected host. Yang et al. (8) show that the ErbB inhibitor CI-1033 greatly reduces the release of EEV from cells infected with either vaccinia or variola. This reduction in EEV release is likely due, at least in part, to inhibition of the viral GF activation of ErbB-1 because, even in the absence of CI-1033, deletion of the GF gene from vaccinia virus has an effect on the release of EEV similar to that of CI-1033 on wild-type virus. However, the drug appears to have additional antiviral effects when added to cells infected with mutant virus as shown by the reduction in the size of plaques. It has recently been shown that actin tail formation, which appears to be involved in EEV release, is regulated by phosphorylation of the viral morphogenesis protein A36 by cellular Src (c-Src) (14, 15). Since activated ErbB-1 is known to activate c-Src (16), this provides one possible explanation for the role of GF in EEV release. Other possible targets for GF-activated ErbB-1 are indicated in Figure 1.
Figure 1Possible mechanism for SPGF-dependent pathogenesis of variola virus and the inhibitory effect of CI-1033. SPGF binds to the ErbB-1 receptor, inducing dimerization and activation. Active phosphorylation of relevant receptors, through unknown mechanisms, may render the cell permissive for viral replication. Phosphorylated ErbB-1 can also activate c-Src kinase as well as the actin polymerization complex, which regulates the formation of actin tails within the cytoplasm. c-Src in turn activates the viral A36 protein, an event required for activation of the actin polymerization complex. Viral replication yields IMVs, which are released from the host cell through cell death and lysis. Alternatively, IMV particles are transported via microtubules and wrapped with additional membrane and protein components to form intracellular-enveloped virus (IEV) particles. IEVs are transported to the cell membrane where they fuse with the plasma membrane to become cellular-enveloped virus (CEV) particles and activate the actin polymerization complex. Some CEVs are released from the cell as EEV particles, which rapidly disseminate the infection. CI-1033 can block the phosphorylation of ErbB-1 and subsequent c-Src activation as well as activation of the actin polymerization complex, which as Yang et al. (8) speculate, may play a role in viral extrusion. CI-1033 may also interfere with events that render cells permissive for viral replication. Figure adapted with permission from Science (15) and Virus Research (13).
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