SUMMARYA rimantadine-resistant variant of the Texas strain of influenza virus (Tr) was obtained by serial passages in eggs and in MDCK cells in the presence of the drug, and its uncoating in MDCK cells was compared to that of the sensitive variant (Ts). First and second steps of uncoating were defined respectively by the appearance of subviral particles (SVP) in nuclear-associated cytoplasm (NAC) and ribonucleoproteins (RNPs) in nucleoplasm. In cells infected with Ts, SVP and RNPs were revealed in NAC, while in the presence of rimantadine RNPs were neither found in NAC nor in the nucleoplasm. In cells infected with Tr, SVP but not RNPs were observed in NAC. The amount of RNPs in the nucleoplasm was almost unchanged in rimantadine-treated cells, demonstrating that rimantadine did not interfere with uncoating of the resistant variant. These findings confirm the suggestion that rimantadine blocks the second step of uncoating of sensitive influenza viruses, and are consistent with the idea that this event does account for the prevention of influenza virus infection by the drug.
Recombinant DNA-produced human interferon-alpha 2 inhibited the replication of influenza A and B viruses in primary rhesus monkey kidney cells (RMK). Human interferon-alpha 2 interacted additively or synergistically with rimantadine hydrochloride or ribavirin in reducing the yield of clinical isolates of either H3N2 or H1N1 subtype influenza A viruses. The combination of human interferon-alpha 2 and ribavirin also inhibited the replication of an influenza B virus to a greater extent than either single agent. In addition to drug concentration, the virus inoculum and duration of culture were important variables in determining the degree of inhibition. Single drugs or combinations did not significantly inhibit the growth of uninfected RMK cells, which indicated that the observed interactions with respect to antiviral activity were not due to cell cytotoxicity.
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