Beyond Receptor Binding: Unexpected Mechanisms of HIV Resistance to eCD4-Ig

This study documents the first evidence of HIV envelope evolution conferring resistance to eCD4-Ig, a promising entry inhibitor that mimics both CD4 and CCR5 receptors. In SHIV-infected rhesus macaques treated with AAV-delivered eCD4-Ig, we observed persistent viremia despite high inhibitor concentrations—indicating the emergence of resistance. Remarkably, just three mutations (R315G, A436T, G471E) conferred substantial eCD4-Ig resistance while significantly reducing viral fitness. Most surprisingly, this resistance employed a previously undescribed mechanism: rather than altering receptor binding sites, the virus evolved to modify envelope protein stability and "triggerability." This discovery reveals an unexpected evolutionary pathway that HIV can exploit to escape broad-spectrum inhibitors, providing crucial insights for designing next-generation entry inhibitors with higher barriers to resistance, and highlighting the remarkable adaptability of HIV even against dual-mimetic inhibitors.

Title: In vivo evolution of env in SHIV-AD8EO-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig

https://doi.org/10.1016/j.ymthe.2024.12.015