HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains

• Type of Material: Article
• Authors: Ashwanth Francis, Emory University; Mariana Marin, Emory University; Parmit K. Singh, Dana Farber Cancer Institute; Vasudevan Achuthan, Dana Farber Cancer Institute; Mathew J. Prellberg, Emory University; Kristina Palermino-Rowland, Emory University; Shuiyun Lan, Emory University; Philip Tedbury, Emory University; Stefan Sarafianos, Emory University; Alan Engelman, Dana Farber Cancer Institute; Gregory Melikian, Emory University
• Language: English
• Date: 2020-07-14
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020, corrected publication 2020
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17256-8
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 3505
• End Page: 3505
• Grant/Funding Information: This work was supported by NIH R01AI129862 grant to G.B.M., R01AI052014 (to A.N.E.), and AI148382, AI120860, and U54 AI150472 (to S.G.S.).
• Keywords: Specificity; Reveal; Enhancers; Infection; Science & Technology; Transcription; Multidisciplinary Sciences; Immunodeficiency virus type 1; Alignment; Active genes; Capsid protein; SAMHD1; Science & Technology - Other Topics
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology; Health Sciences, Immunology; Chemistry, Biochemistry

Abstract

The early steps of HIV-1 infection, such as uncoating, reverse transcription, nuclear import, and transport to integration sites are incompletely understood. Here, we imaged nuclear entry and transport of HIV-1 replication complexes in cell lines, primary monocyte-derived macrophages (MDMs) and CD4+ T cells. We show that viral replication complexes traffic to and accumulate within nuclear speckles and that these steps precede the completion of viral DNA synthesis. HIV-1 transport to nuclear speckles is dependent on the interaction of the capsid proteins with host cleavage and polyadenylation specificity factor 6 (CPSF6), which is also required to stabilize the association of the viral replication complexes with nuclear speckles. Importantly, integration site analyses reveal a strong preference for HIV-1 to integrate into speckle-associated genomic domains. Collectively, our results demonstrate that nuclear speckles provide an architectural basis for nuclear homing of HIV-1 replication complexes and subsequent integration into associated genomic loci.