CONCLUDING REMARKS
In this review, we have attempted to summarize the present state and perspectives of antiviral therapy for arenavirus infections in relation to the dramatic increase in virus emergence during the last decade. Because of the very high case-fatality rates in patients with Lassa fever and the continuing appearance of new viruses in North and South America, including agents responsible for severe human infections, control through chemotherapy warrants special attention.
The replicative cycle of arenaviruses comports a number of steps that could be considered adequate targets for chemotherapeutic interventions reviewed here, numerous compounds have been reported to inhibit the replication of arenaviruses acting at the early stages of attachment and entry, the biosynthetic processes of replication and transcription, or the late steps of maturation, exocytosis, and budding.
Although these studies have brought a better understanding of the mechanisms of virus multiplication and the interaction with the host cell, very few successes on true therapeutic possibilities have been obtained. As occurs with other viruses, the most explored approach of antiviral development has been the utilization of different kinds of nucleoside analogues to block viral RNA transcription and/or replication. However, all the nucleoside analogues tested against arenaviruses up to now have the serious drawback of a considerable level of toxicity and, in considering the equilibrium risk-benefit ratio, ribavirin is still accepted at present as the most valuable chemotherapeutic agent for arenavirus treatment. It must be remarked that so far the best therapy for Argentine hemorrhagic fever patients is the administration of convalescent plasma.
The methods used to discover antiviral drugs have evolved considerably over recent years, particularly driven by the medical need for effective compounds for the treatment of diseases associated with HIV. The traditional methodology of in vitro screening of compounds against a particular target has been the only strategy employed against arenaviruses. An alternative approach based on using high-resolution structural data on target biomolecules to design compounds has not be applied in Arenaviridae due to the lack of studies on the crystal structure of the virus component candidates as substrates.
Numerous efforts have also been devoted to obtaining safe vaccines to protect the population against hemorrhagic fever agents. In fact, an attenuated live vaccine named Candid 1 has been developed for Argentine hemorrhagic fever (Maiztegui et al., 1998) and has been evaluated in the human population of the endemic area. However, vaccines probably will never be the complete answer to the control of arenavirus infections. Even with an effective vaccine, occasional outbreaks are expected to occur due to the characteristics of the viruses, for example, because of ecological changes in the habits of the natural rodent reservoir. In addition, the appearance of novel strains or virus species not cross-reacting with vaccine components may lead to the production of isolated cases, outbreaks, or epidemics, all health-threatening situations requiring the administration of an effective chemotherapy.