The HIV-1 Budding Machinery: Deconstructing the ESCRT-Mediated Scission Pathway

Human immunodeficiency virus type 1 (HIV-1) exploits the host endosomal sorting complexes required for transport (ESCRT) machinery to mediate the final step of its life cycle—virion budding and membrane scission. This review provides a comprehensive synthesis of current molecular and structural insights into the hierarchical recruitment and functional integration of ESCRT components by the viral Gag polyprotein. Particular emphasis is placed on the PTAP and YPXₙL late domain motifs within the p6 region of Gag, which engage distinct adaptor proteins, Tsg101 (ESCRT-I) and ALIX, to orchestrate the ordered assembly of downstream ESCRT-III polymers and the VPS4 ATPase that catalyzes membrane fission. The review further delineates the redundancy and adaptability of these recruitment pathways, the modulatory role of ubiquitin signaling, and the influence of membrane composition and cellular context on budding efficiency. Emerging data linking ESCRT function to viral persistence, immune evasion, and therapeutic susceptibility are critically evaluated. Unresolved mechanistic questions concerning ESCRT-III dynamics, VPS4-driven remodeling, and the spatial regulation of scission events are also identified. Collectively, this analysis establishes an integrated conceptual framework for understanding ESCRT-dependent HIV-1 egress and highlights potential molecular interfaces for targeted antiviral intervention.