Molecular basis of attenuation

A reduction in pathogenicity can occur either through the loss of external pathogenic factors (toxins), as is the case with some bacterial vaccines, or by impairing the invasiveness of a pathogen and limiting its access to target organs. In many cases attenuating mutations occur in capsid or envelope proteins of a virus, presumably reducing its affinity for the target cells. Detailed studies of attenuated polioviruses identified a number of mutations that distinguished vaccine viruses from their wild-type progenitor strains. The mutations linked to attenuation were located in genes for both capsid and non-capsid proteins, as well as in the untranslated regulatory regions (UTRs) of the genome. The mutations in a stem-and-loop domain within the internal ribo-some entry site (IRES) of the 5'-UTRs were responsible for the attenuation of all three types of polio-virus. These mutations impaired the initiation of viral protein synthesis by decreasing the affinity of viral RNA to cellular initiation factors. This impairment was cell-type specific, as the difference in rep-licative capacity between attenuated and wild-type strains was much more pronounced in cultures of cells of neuronal origin than in those of nonneuronal cells.

Viruses serially passaged in vitro or isolated from recipients of OPV were found to have reverted at some of the attenuated sites (including the one in the IRES) back to the wild-type state. Other mutations were found which boosted the replicative capacity of the attenuated strains in vitro but did not contribute to increased neurovirulence in monkeys. While attenuation is generally associated with lowering the replicative capacity, 'weakening' of the virus does not necessarily lead to a loss of pathogenicity. Attenuation is linked to an inability of the virus to replicate in specific target cells (motor neurons in the case of poliovirus), while retaining the ability to replicate in noncritical organs.

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