R5 HIV env and Vesicular Stomatitis Virus G Protein Cooperate To Mediate Fusion to Naive CD4 ⁺ T Cells

Naïve CD4(4) T cells are resistant to both HIV R5 env and vesicular stomatitis virus G protein (VSV-G)-mediated fusion. However, viral particles carrying both HIV R5 env and VSV-G infect naïve cells by an unexplained mechanism. We show that VSV-G-pseudotyped virus cannot fuse to unstimulated cells because the viral particles cannot be endocytosed. However, virions carrying both HIV R5 env and VSV-G can fuse because CD4 binding allows viral uptake. Our findings reveal a unique mechanism by which R5 HIV env and VSV-G cooperate to allow entry to naïve CD4(+) T cells, providing a tool to target naïve CD4(+) T cells with R5 HIV to study HIV coreceptor signaling and latency.