Cyclophilin A protects HIV-1 from restriction by human TRIM5a. Journal Article

Authors: Kim, K; Dauphin, A; Komurlu, S; McCauley, SM; Yurkovetskiy, L; Carbone, C; Diehl, WE; Strambio-De-Castillia, C; Campbell, EM; Luban, J
Article Title: Cyclophilin A protects HIV-1 from restriction by human TRIM5a.
Abstract: The HIV-1 capsid (CA) protein lattice encases viral genomic RNA and regulates steps essential to target-cell invasion. Cyclophilin A (CypA) has interacted with the CA of lentiviruses related to HIV-1 for millions of years. Disruption of the CA-CypA interaction decreases HIV-1 infectivity in human cells but stimulates infectivity in non-human primate cells. Genetic and biochemical data suggest that CypA protects HIV-1 from a CA-specific restriction factor in human cells. Discovery of the CA-specific restriction factor tripartite-containing motif 5a (TRIM5a) and multiple, independently derived, TRIM5-CypA fusion genes pointed to human TRIM5a being the CypA-sensitive restriction factor. However, HIV-1 restriction by human TRIM5a in tumour cell lines is minimal and inhibition of such activity by CypA has not been detected. 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 TRIM5a, with the block occurring before reverse transcription. Endogenous TRIM5a 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 TRIM5a.
Journal Title: Nature microbiology
Publisher: Unknown  
Date Published: 2019