Immunological effects of the orally administered neuraminidase inhibitor oseltamivir in influenza virus-infected and uninfected mice

Oseltamivir (GS4104), the ethyl ester prodrug of the carbocyclic transition state sialic acid analog GS4071, has been reported to be a striking inhibi tor of influenza A and B virus infections in mice and ferrets. Multiple stu dies indicate this material to also be active against the disease in humans , and it has recently been approved for human use. The effect of oral gavag e (p.o.) therapy of oseltamivir on various immune factors considered to be of importance in primary influenza virus infection was studied in mice. Bot h uninfected animals and those infected with influenza A/NWS/33 (H1N1) viru s were used. Doses of 100 mg kg(-1) day(-1) were administered twice daily f or 5 days beginning 16 h pre-virus exposure. Two hours after end of treatme nt, the mice were killed and their spleens assayed for cytotoxic T lymphocy te (CTL) and natural killer (NK) cell activity. Subpopulations of splenic T , T-helper, T-cytotoxic and B lymphocytes as well as macrophages were deter mined using flow cytometry. Similar significant (P < 0.01) increases in CTL activity were seen at effector:target cell ratios of 60:1 and 30:1 in the infected mice treated with oseltamivir or with placebo. NK cell activity wa s greater in the infected mice than in uninfected mice; the levels in all a nimals were not significantly affected by treatment with oseltamivir. Macro phage, T, T-helper, T-cytotoxic and B lymphocyte populations were similar i n both treated and untreated animals. These data indicate treatment with os eltamivir does not adversely affect the primary in vivo cellular immune res ponses to influenza virus infection assayed in this study. The experiment w as repeated to show that treatment with this compound significantly prevent ed the development of the infection and inhibited virus titers in the lung. Surviving treated mice on day 21 had mean neutralizing antibody titers of 1:208, and withstood rechallenge with the virus at this time, indicating th e initial virus-inhibitory effect also did not prevent the animals from dev eloping an adequate humoral immunity to the virus. (C) 2000 Elsevier Scienc e B.V. All rights reserved.