Arenaviruses can cause severe hemorrhagic fever in humans. There are currently no FDA-approved vaccines or drugs to battle arenavirus infection. The mechanism of arenavirus-cell fusion mediated by the glycoprotein complex (GPC) is not well understood. We employ single-virus labeling and imaging tools to examine entry pathways and the fusion mechanism of arenaviruses, such as Lassa, LCMV, and Junin viruses. We found that arenavirus fusion is uniquely preceded by an obligatory viral membrane permeabilization step (Figure 6 and Movie 3) (Zhang et al., 2023), which we hypothesize to promote subsequent uncoating of the viral nucleoprotein. This permeabilization step is caused by fusogenic conformational changes of GPC, which thus appears to exhibit a viroporin-like activity. We also discovered that the late endosome-resident lipid, BMP, specifically promotes late steps of arenavirus fusion (Zhang, Carlos de la Torre, and Melikyan, 2022).
