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

DOI: 10.1128/mBio.03142-20 DOI Help

Authors: Zhou Zhong (University of Pittsburgh School of Medicine) , Jiying Ning (University of Pittsburgh School of Medicine) , Emerson A. Boggs (University of Pittsburgh School of Medicine) , Sooin Jang (University of Pittsburgh School of Medicine; Harvard Medical School) , Callen Wallace (University of Pittsburgh School of Medicine) , Cheryl Telmer (Carnegie Mellon University) , Marcel P. Bruchez (Carnegie Mellon University) , Jinwoo Ahn (University of Pittsburgh School of Medicine) , Alan N. Engelman (University of Pittsburgh School of Medicine; Dana-Farber Cancer Institute; Harvard Medical School) , Peijun Zhang (University of Pittsburgh School of Medicine; Wellcome Trust Centre for Human Genetics, University of Oxford; Diamond Light Source) , Simon C. Watkins (University of Pittsburgh School of Medicine) , Zandrea Ambrose (University of Pittsburgh School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio , VOL 12

State: Published (Approved)
Published: April 2021

Open Access Open Access

Abstract: Human 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 cotraffic 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 assemblies in 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 variations in HIV-1 capsid trafficking and uncoating in CD4+ T cells and macrophages.

Journal Keywords: CPSF6; capsid; cyclophilin A; human immunodeficiency virus; live-cell imaging; microtubule

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Technical Areas:

Documents:
mBio-2021-Zhong-e03142-20.full.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Infectious Diseases Pathogens

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