The precise timing and location of uncoating (early vs. late endosomes) depends on the pH-mediated transition of the specific viral hemagglutinin (HA) molecule involved. The uncoating of influenza viruses in endosomes is blocked by changes in pH caused by weak bases (e.g. ammonium chloride and chloroquine) or ionophores (e.g. monensin). Effective uncoating is also dependent on the presence of the viral M2 ion channel protein. Early on it was recognized that amantadine and rimantadine inhibit replication immediately following virus infection. Later it was found that the virus-associated M2 protein allows the influx of H+ ions into the virion, which disrupts protein-protein interactions, resulting in the release of viral RNP free of the viral matrix (M1) protein. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus uncoating. The HA mediated fusion of the viral membrane with the endosomal membrane and the M2-mediated release of the RNP results in the appearance of free RNP complexes in the cytosol. This completes the uncoating process. The time frame for the uncoating process has been examined by inhibiting virus penetration with ammonium chloride. Typically, virus particles show a penetration half time of about 25 minutes after viral adsorption. Ten minutes later (half time of 34 minutes after adsorption) RNP complexes are found in the nucleus. Uptake of RNP molecules through nuclear pores is an active process, involving the nucleo-cytoplasmic trafficking machinery of the host cell.