Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport

• Type of Material: Article
• Authors: Ashwanth Francis, Emory University; G.B. Melikyan, Emory University
• Language: English
• Date: 2018-04-11
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chom.2018.03.009
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 23
• Issue: 4
• Start Page: 536
• End Page: +
• Grant/Funding Information: This work was supported by the NIH R01 GM054787 and AI129862 grants to GBM.
• Keywords: RECOGNITION; GAG PROTEIN; Parasitology; CYCLOPHILIN; COMPLEXES; CELLS; Microbiology; HOST PROTEINS; Virology; REPLICATION; IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE TRANSCRIPTION; Science & Technology; Life Sciences & Biomedicine; COMPLEMENTARY ASSAYS REVEAL
• Research Categories: Biology, Virology; Health Sciences, Medicine and Surgery

Abstract

The HIV-1 core consists of capsid proteins (CA) surrounding viral genomic RNA. After virus-cell fusion, the core enters the cytoplasm and the capsid shell is lost through uncoating. CA loss precedes nuclear import and HIV integration into the host genome, but the timing and location of uncoating remain unclear. By visualizing single HIV-1 infection, we find that CA is required for core docking at the nuclear envelope (NE), whereas early uncoating in the cytoplasm promotes proteasomal degradation of viral complexes. Only docked cores exhibiting accelerated loss of CA at the NE enter the nucleus. Interestingly, a CA mutation (N74D) altering virus engagement of host factors involved in nuclear transport does not alter the uncoating site at the NE but reduces the nuclear penetration depth. Thus, CA protects HIV-1 complexes from degradation, mediates docking at the nuclear pore before uncoating, and determines the depth of nuclear penetration en route to integration. HIV-1 genome is enclosed in a capsid shell composed of CA proteins. By imaging virions labeled with a fluorescent CA marker, Francis and Melikyan reveal that premature CA loss leads to proteasomal degradation of viral complexes, whereas CA release at the nuclear pore results in nuclear entry and productive integration.