Targeted CPSF6 recoding reveals global fitness advantages of SPAD integration targeting and cell type-specific roles for capsid binding in HIV-1 DNA synthesis and nuclear import.

Targeted CPSF6 capsid-binding recoding (F/G to A/A) ablates a global fitness advantage linked to HIV-1 DNA integration into speckle-associated domains across CD4-positive Jurkat T, CEM12D7 T, and THP-1 myeloid/macrophage cells.

• Why it matters: CPSF6 depletion confounds HIV-1 phenotypes because CPSF6 also regulates alternative polyadenylation, making it unclear which effects reflect capsid binding versus RNA-processing changes.
• What they did: Using CRISPR/Cas9 homology-directed repair, the authors endogenously recoded the CPSF6 capsid-binding phenylalanine-glycine motif to alanine-alanine in CD4-positive Jurkat T cells, CEM12D7 T cells, and THP-1 myeloid/macrophage cells, then compared infection, reverse transcription, and nuclear import.
• The result: En masse, recoded T cells showed reduced HIV-1 replication consistent with loss of integration-linked fitness, while recoded myeloid/macrophage cells had reduced single-round infection correlated with decreased reverse transcription and more robust nuclear import blocks, without evidence of enhanced type I interferon production or sensing.

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