Cytoplasmic CPSF6 regulates HIV-1 capsid trafficking and infection in a cyclophilin A-dependent manner

• DOI: 10.1101/2020.06.05.136697
• Publication Date: 2020-06-06T10:55:12Z
• Authors: Zhou Zhong; Jiying Ning; Emerson A. Boggs; Sooin Jang; Callen Wallace; Cheryl Telmer; Marcel P. Bruchez; Jinwoo Ahn; Alan N. Engelman; Peijun Zhang; Simon C. Watkins; Zandrea Ambrose
• Keywords: CD4-Positive T-Lymphocytes; Cell Nucleus; mRNA Cleavage and Polyadenylation Factors; 0301 basic medicine; 0303 health sciences; Macrophages; Virus Replication; Microbiology; QR1-502; Immunity, Innate; 3. Good health; 03 medical and health sciences; Capsid; HEK293 Cells; Host-Pathogen Interactions; HIV-1; Humans; Capsid Proteins; Cyclophilin A; Research Article; HeLa Cells

SummaryHuman immunodeficiency virus type 1 (HIV-1) capsid binds host proteins during infection, including cleavage and polyadenylation specificity factor 6 (CPSF6) and cyclophilin A (CypA). We observe that HIV-1 infection induces higher-order CPSF6 formation and capsid-CPSF6 complexes co-traffic on microtubules. CPSF6-capsid complex trafficking is impacted by capsid alterations that reduce CPSF6 binding or by excess cytoplasmic CPSF6 expression, both of which are associated with decreased HIV-1 infection. Higher-order CPSF6 complexes bind and disrupt HIV-1 capsid assembliesin vitro. Disruption of HIV-1 capsid binding to CypA leads to increased CPSF6 binding and altered capsid trafficking, resulting in reduced infectivity. Our data reveal an interplay between CPSF6 and CypA that is important for cytoplasmic capsid trafficking and HIV-1 infection. We propose that CypA prevents HIV-1 capsid from prematurely engaging cytoplasmic CPSF6 and that differences in CypA cellular localization and innate immunity may explain cell-specific variations in HIV-1 capsid trafficking and uncoating.Graphical Abstract