Dominant drug targets suppress the emergence of antiviral resistance.

The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.

From emergence to eradication: the epidemiology of poliomyelitis deconstructed.

Poliomyelitis has appeared in epidemic form, become endemic on a global scale, and been reduced to near-elimination, all within the span of documented medical history. Epidemics of the disease appeared in the late 19th century in many European countries and North America, following which polio became a global disease with annual epidemics. During the period of its epidemicity, 1900-1950, the age distribution of poliomyelitis cases increased gradually. Beginning in 1955, the creation of poliovirus vaccines led to a stepwise reduction in poliomyelitis, culminating in the unpredicted elimination of wild polioviruses in the United States by 1972. Global expansion of polio immunization resulted in a reduction of paralytic disease from an estimated annual prevaccine level of at least 600,000 cases to fewer than 1,000 cases in 2000. Indigenous wild type 2 poliovirus was eradicated in 1999, but unbroken localized circulation of poliovirus types 1 and 3 continues in 4 countries in Asia and Africa. Current challenges to the final eradication of paralytic poliomyelitis include the continued transmission of wild polioviruses in endemic reservoirs, reinfection of polio-free areas, outbreaks due to circulating vaccine-derived polioviruses, and persistent excretion of vaccine-derived poliovirus by a few vaccinees with B-cell immunodeficiencies. Beyond the current efforts to eradicate the last remaining wild polioviruses, global eradication efforts must safely navigate through an unprecedented series of endgame challenges to assure the permanent cessation of all human poliovirus infections.

Annual report of the Australian National Poliovirus Reference Laboratory 2005.

In May 1988 the World Health Assembly adopted a resolution for the global eradication of poliomyelitis. Since then two target dates for eradication (2000 and 2003) have passed and the struggle to eradicate the poliovirus continues. Australia's commitment to the worldwide campaign began in December 1994 with the designation of the National Poliovirus Reference Laboratory at the Victorian Infectious Diseases Reference Laboratory and the initiation of acute flaccid paralysis (AFP) surveillance in March 1995. During 2005 the National Poliovirus Reference Laboratory did not isolate any wild or vaccine derived polioviruses from the 42 samples collected from eighteen cases of acute flaccid paralysis in Australian residents. Three Sabin-like polioviruses were isolated from three cases of acute flaccid paralysis but all were considered incidental isolations by the Polio Expert Committee and not implicated in the disease of the patients. After exceeding the World Health Organization target of one case of AFP per 100,000 children aged less than 15 years in 2004, Australia's non-polio AFP rate in 2005 fell to 0.75 cases per 100,000 children. The high number of wild poliovirus importations reported globally in 2005 into previously polio free countries, highlights the need for a sensitive AFP surveillance system within Australia and for specimens from AFP cases to be forwarded to the National Poliovirus Reference Laboratory.

Annual report of the Australian National Poliovirus Reference Laboratory, 2002.

Acute flaccid paralysis is the main clinical manifestation of poliomyelitis. Faecal specimens from cases of acute flaccid paralysis in Australia are referred to the National Poliovirus Reference Laboratory for virus culture to determine if poliovirus is the causative agent. Isolations of poliovirus are tested to determine whether they have characteristics of the Sabin oral polio vaccine virus strains or wild type polioviruses. In 2002, a poliovirus type 3, which tested as Sabin vaccine-like, was isolated from an Australian patient with acute flaccid paralysis. A non-polio enterovirus, Echovirus type 18, was isolated from the faecal specimens of another case of acute flaccid paralysis. In the same period, the laboratory identified 35 Sabin-like polioviruses from 52 referred specimens and isolates from cases without acute flaccid paralysis. Australia is a member nation of the World Health Organization's Western Pacific region that was declared free of endemic wild poliovirus in October 2000. Poliomyelitis remains endemic in three of the WHO regions of the world and wild poliovirus may be re-introduced to Australia. While the number of polio-endemic countries has been reduced to seven, the total number of wild polioviruses identified increased in 2002 compared to 2001 due to a sharp rise in isolations of wild virus from Northern India. Until global eradication of poliomyelitis is achieved, it is essential that a high level of poliovirus vaccination coverage, and surveillance for cases of acute flaccid paralysis, be maintained in Australia.

In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus.

Chrysophanic acid (1,8-dihydroxy-3-methylanthraquinone), isolated from the Australian Aboriginal medicinal plant Dianella longifolia, has been found to inhibit the replication of poliovirus types 2 and 3 (Picornaviridae) in vitro. The compound inhibited poliovirus-induced cytopathic effects in BGM (Buffalo green monkey) kidney cells at a 50% effective concentration of 0.21 and 0.02 microgram/ml for poliovirus types 2 and 3, respectively. The compound inhibited an early stage in the viral replication cycle, but did not have an irreversible virucidal effect on poliovirus particles. Chrysophanic acid did not have significant antiviral activity against five other viruses tested: Coxsackievirus types A21 and B4, human rhinovirus type 2 (Picornaviridae), and the enveloped viruses Ross River virus (Togaviridae) and herpes simplex virus type 1 (Herpesviridae). Four structurally-related anthraquinones--rhein, 1,8-dihydroxyanthraquinone, emodin and aloe-emodin were also tested for activity against poliovirus type 3. None of the four compounds was as active as chrysophanic acid against the virus. The results suggested that two hydrophobic positions on the chrysophanic acid molecule (C-6 and the methyl group attached to C-3) were important for the compound's activity against poliovirus.