Cyclophilin A protects HIV-1 from restriction by human TRIM5alpha
Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Immunology and Infectious Disease | Microbiology | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Viruses
The HIV-1 capsid (CA) protein lattice encases viral genomic RNA and regulates steps essential to target-cell invasion(1). 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 5alpha (TRIM5alpha)(21) and multiple, independently derived, TRIM5-CypA fusion genes(4,5,15,22-26) pointed to human TRIM5alpha being the CypA-sensitive restriction factor. However, HIV-1 restriction by human TRIM5alpha in tumour cell lines is minimal(21) and inhibition of such activity by CypA has not been detected(27). 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 TRIM5alpha, with the block occurring before reverse transcription. Endogenous TRIM5alpha 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 TRIM5alpha.
Infection, Molecular medicine, RNAi
DOI of Published Version
Kim K, Dauphin A, Komurlu S, McCauley SM, Yurkovetskiy L, Carbone C, Diehl WE, Strambio-De-Castillia C, Campbell EM, Luban J. Cyclophilin A protects HIV-1 from restriction by human TRIM5α. Nat Microbiol. 2019 Dec;4(12):2044-2051. doi: 10.1038/s41564-019-0592-5. Epub 2019 Oct 21. PMID: 31636416; PMCID: PMC6879858. Link to article on publisher's site
Kim K, Dauphin A, Komurlu S, McCauley SM, Yurkovetskiy L, Carbone C, Diehl WE, Strambio-De-Castilla C, Campbell EM, Luban J. (2019). Cyclophilin A protects HIV-1 from restriction by human TRIM5alpha. Program in Molecular Medicine Publications and Presentations. https://doi.org/10.1038/s41564-019-0592-5. Retrieved from https://escholarship.umassmed.edu/pmm_pp/145