The mutability of HIV has been mentioned repeatedly during the HIV disease pandemic, raising questions about how broad a biological change the virus might undergo (Vartanian et al., 1991). It is important to make a distinction between point mutations—to which HIV is prone—and changes in pathogenic properties, such as initiation of infection, that would influence host range and mode of transmission. HIV does undergo frequent point mutations, especially in regions of the genome that are likely to be targeted by vaccines (Phillips et al., 1991). Although it is theoretically possible that such a change could alter its infective properties, the stability of other RNA viruses, with regard to host and organ specificity, indicates that this possibility is unlikely. Also reassuring is the general experience that evolutionary adaptation of pathogens tends toward lesser virulence.
Hepatitis B is a DNA virus, but because it uses reverse transcriptase to replicate, it shares with RNA viruses the tendency to undergo significant and rapid genetic change. In recent years, a number of rare viral variants have been identified in patients infected with hepatitis B. These have generally fallen into two categories: variants with truncated protein products ("precore" and "pre-S" variants) and vaccine escape mutants.
The precore and pre-S variants have mutations in regions of DNA that immediately precede the coding sequences for certain viral proteins (core or surface protein, respectively). The mutations cause a truncated product to be manufactured and also appear to alter pathogenesis, especially in the case of precore variants (Neurath and Kent, 1988; Carman et al., 1991; Liang et al., 1991; Omata et al., 1991). The precore region of the hepatitis B virus is not required for the production of viral particles. Precore mutants thus are viable but lack the viral antigen known as HBeAg, which is a key component of some diagnostic tests. This variant was first isolated in patients in Italy and Greece who had an unusual form of severe chronic hepatitis but were negative for HBeAg (Carman et al., 1989; Carman et al., 1991). Since then, the precore variant has also been isolated from patients with fulminant acute hepatitis B infection (Carman et al., 1991; Liang et al., 1991; Omata et al., 1991).
In one study in Japan (Omata et al., 1991), nine patients with either acute fulminant hepatitis B infection (five patients) or severe exacerbation of chronic hepatitis B (four patients) were tested. Hepatitis B virus was successfully recovered from seven of the nine patients, and a precore variant with the identical nonsense (terminating) mutation was isolated. This variant was not found in 10 controls with acute, self-limited hepatitis B. In