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

Ashwanth C. Francis (), Mariana Marin, Parmit K. Singh, Vasudevan Achuthan, Mathew J. Prellberg, Kristina Palermino-Rowland, Shuiyun Lan, Philip R. Tedbury, Stefan G. Sarafianos, Alan N. Engelman and Gregory B. Melikyan ()
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Ashwanth C. Francis: Emory University School of Medicine
Mariana Marin: Emory University School of Medicine
Parmit K. Singh: Dana-Farber Cancer Institute
Vasudevan Achuthan: Dana-Farber Cancer Institute
Mathew J. Prellberg: Emory University School of Medicine
Kristina Palermino-Rowland: Emory University School of Medicine
Shuiyun Lan: Emory University School of Medicine
Philip R. Tedbury: Emory University School of Medicine
Stefan G. Sarafianos: Emory University School of Medicine
Alan N. Engelman: Dana-Farber Cancer Institute
Gregory B. Melikyan: Emory University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17256-8

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