Cyclophilin A protects HIV-1 from restriction by human TRIM5α

The HIV-1 capsid (CA) protein lattice encases viral genomic RNA and regulates steps essential to target-cell invasion¹. Cyclophilin A (CypA) has interacted with the CA of lentiviruses related to HIV-1 for millions of years^2-7. Disruption of the CA-CypA interaction decreases HIV-1 infectivity in human cells^8-12 but stimulates infectivity in non-human primate cells^13-15. Genetic and biochemical data suggest that CypA protects HIV-1 from a CA-specific restriction factor in human cells^16-20. Discovery of the CA-specific restriction factor tripartite-containing motif 5α (TRIM5α)²¹ and multiple, independently derived, TRIM5-CypA fusion genes^4,5,15,22-26 pointed to human TRIM5α being the CypA-sensitive restriction factor. However, HIV-1 restriction by human TRIM5α in tumour cell lines is minimal²¹ and inhibition of such activity by CypA has not been detected²⁷. Here, by exploiting reverse genetic tools optimized for primary human blood cells, we demonstrate that disruption of the CA-CypA interaction renders HIV-1 susceptible to potent restriction by human TRIM5α, with the block occurring before reverse transcription. Endogenous TRIM5α associated with virion cores as they entered the cytoplasm, but only when the CA-CypA interaction was disrupted. These experiments resolve the long-standing mystery of the role of CypA in HIV-1 replication by demonstrating that this ubiquitous cellular protein shields HIV-1 from previously inapparent restriction by human TRIM5α.