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

• 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
• Journal Title: Nature Communications
• Volume: Volume 11, Number 1
• Publisher: Nature Portfolio | 2020-07-14, Pages 3505-3505
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-020-17256-8
• Subjects: Health Sciences, Immunology; Health Sciences, Oncology; Chemistry, Biochemistry; Health Sciences, Pharmacology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Immunodeficiency virus type 1; Capsid protein; Active genes; Transcription; Specificity; Enhancers; Infection; Alignment; SAMHD1; Reveal

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.