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bioRxiv · 10.64898/2026.01.10.698794

A Hybrid Gag Lattice as a Structural Intermediate in HIV-1 Maturation

Meuser, M. E.·Wu, C.·Macke, A. C.·Shi, J.·Cheng, J.·Yang, R. R.·Freniere, C.·Lin, J.·Aiken, C.·Perilla, J. R.·Xiong, Y.
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Abstract

HIV-1 maturation converts the spherical immature Gag lattice into the conical mature capsid required for infectivity, yet the structural route linking these two lattice endpoints remains unclear. Using single-particle cryo-electron microscopy and cryo-electron tomography on reconstituted assemblies and virus-like particles (VLPs), we identify a distinct hybrid lattice in which the capsid protein (CA) N-terminal domain adopts a mature-like conformation, whereas the CA C-terminal domain-SP1 layer remains immature. This architecture is observed in native, enveloped VLPs produced in human cells, demonstrating formation under physiologically relevant conditions. The hybrid lattice engages three myo-inositol hexakisphosphate (IP6) molecules per CA-SP1 hexamer, underscoring IP6-dependent stabilization; accordingly, excess IP6 enriches the hybrid population. Tomographic mapping shows that hybrid regions coexist with the immature lattice within the same particle and are enriched near lattice discontinuities, consistent with edge-localized remodeling that can accommodate conformational rearrangements and partial disassembly and reassembly. Disrupting a hybrid-specific inter-hexamer contact preserves immature lattice assembly and particle release but abrogates infectivity, compromises core integrity, and prevents mature lattice formation, implicating the hybrid architecture as an on-pathway intermediate. Molecular dynamics simulations further support coordinated rearrangements that bias the system away from the immature configuration toward hybrid and then mature organizations. Together, these results support a maturation model in which localized displacive remodeling and partial disassembly/reassembly act in concert, with IP6 tuning the balance among lattice states. This study provides new insight into HIV-1 maturation and identifies the hybrid lattice as a potential therapeutic target.

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Meuser, M. E., Wu, C., Macke, A. C., Shi, J., Cheng, J., Yang, R. R., Freniere, C., Lin, J., Aiken, C., Perilla, J. R., Xiong, Y.. 2026-01-11. A Hybrid Gag Lattice as a Structural Intermediate in HIV-1 Maturation. https://doi.org/10.64898/2026.01.10.698794

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