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| Title | Structural basis of lenacapavir-induced HIV-1 capsid defects during virion maturation. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Sep 22, 2026 |
 Authors | Hiroki Tanaka / Reina Morita / Tomomasa Oka / Minoru Fukushima / Shunsuke Kita / Mina Sasaki / Katsumi Maenaka / Shinichi Machida /  |
| PubMed Abstract | Long-acting lenacapavir (LEN) has emerged as a highly effective, potentially game-changing therapy for HIV treatment and prevention. Its mechanism of action in the early phase of HIV-1 replication, ...Long-acting lenacapavir (LEN) has emerged as a highly effective, potentially game-changing therapy for HIV treatment and prevention. Its mechanism of action in the early phase of HIV-1 replication, when the capsid directs key post-entry steps such as reverse transcription, nuclear import, and integration, has been well characterized. In contrast, its effects during the late phase of replication, when the capsid assembles and matures within budding virions, remain poorly understood. Here, we determine the cryo-electron microscopy structure of the mature HIV-1 capsid lattice assembled within virus-like particles in the presence of LEN. Our structural analyses reveal that LEN alters interhexamer interactions, perturbs the capsid lattice curvature, and thereby prevents the formation of a functional cone-shaped capsid. Biochemical analyses further demonstrate that LEN-containing cores lose reverse transcriptase because of compromised capsid integrity, whereas integrase and viral RNA remain associated. Functionally, viruses produced in the presence of LEN exhibit markedly reduced infectivity, low reverse transcription activity, and poor integration. Taken together, these findings provide mechanistic insights into the late-phase action of LEN and provide key directions for the design of future inhibitors. |
 External links | Nat Commun / PubMed:42773142 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.98 - 6.07 Å |
| Structure data | EMDB-67116, PDB-9xqh: EMDB-81945, PDB-43kn:  EMDB-81946: LEN-bound HIV-1 capsid lattice within VLPs treated with PFO, no symmetry EMDB-81947, PDB-43ko:  EMDB-81948: LEN-unbound HIV-1 capsid lattice within VLPs treated with PFO, no symmetry |
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 Keywords | VIRAL PROTEIN / complex |
human immunodeficiency virus 1