Molecular Characterization of Attenuated Junin Virus Variants

Junin virus. one of the few human pathogenic arenaviruses, is the etiologic agent ot Argentine hemorrhagic fever (AHF). The clinical symptoms of AHF include hematologic. neurologic. cardiovascular. renal and immunologic alterations. The mortality rate may be as high as 30%. but early treatment with immune plasma reduces the fatal cases to less than 2%. In order to control the endemo-epidemics in the richest farming land in Argentina a collaborative effort conducted by US and Argentine Governments led to the production of a live. attenuated Junin virus vaccine. After rigorous biological testing in rhesus monkeys. the highly attenuated Junin virus variant named Candid #1 (CDl) was used in human volunteers. followed by an extensive clinical trial in the AHF endemic area. In order to characterize the vaccine strain COl at the molecular level and initiate studies on the biochemical basis of attenuation of virulence. the structural protein genes of this attenuated virus were cloned and sequenced. In addition. cONA clones of the XJ144 strain -a very close predecessor of CDI- were also analyzed. Several changes in the amino acid sequence of N were observed that alter both the net charge and the predicted secondary structure of this polypeptide. When the attenuated strains XJ144 and CDl were compared to the wild type MC2 strain. major changes in the amino acid sequence were observed in the amino terminal region of glycoprotein precursor gene (GPC) as a result of several insertions and deletions in the nucleotide sequence. After proteolytic cleavage of GPC these alterations appear in the Gi polypeptide. that 5 thought to be located on the surface of the virion in association with the more internal G2 protein. The predicted secondary structures of CDI and XJ#44 GI proteins are similar to each other On the contrary. the G2 protein of COl has a different hydrophobic motif from those of XJ#44 and MC2. which bare a close resemblance t