Structural basis of host protein hijacking in human T-cell leukemia virus integration

Veer Bhatt,Sibes Bera,Ke Shi,Reuben S Harris,Duane P Grandgenett,Hideki Aihara,Kayo Orellana,Daniel J Salamango,Fredy Kurniawan,Anna C Sundborger-Lunna,Nicholas H Moeller,Wei Zhang,Heather O Bohl,Krishan K Pandey

doi:10.1038/s41467-020-16963-6

Abstract

Integration of the reverse-transcribed viral DNA into host chromosomes is a critical step in the life-cycle of retroviruses, including an oncogenic delta(δ)-retrovirus human T-cell leukemia virus type-1 (HTLV-1). Retroviral integrase forms a higher order nucleoprotein assembly (intasome) to catalyze the integration reaction, in which the roles of host factors remain poorly understood. Here, we use cryo-electron microscopy to visualize the HTLV-1 intasome at 3.7-Å resolution. The structure together with functional analyses reveal that the B56γ (B’γ) subunit of an essential host enzyme, protein phosphatase 2 A (PP2A), is repurposed as an integral component of the intasome to mediate HTLV-1 integration. Our studies reveal a key host-virus interaction underlying the replication of an important human pathogen and highlight divergent integration strategies of retroviruses.

Highlights

Integration of the reverse-transcribed viral DNA into host chromosomes is a critical step in the life-cycle of retroviruses, including an oncogenic delta(δ)-retrovirus human T-cell leukemia virus type-1 (HTLV-1)
IN from another lentivirus, and an important retroviral human pathogen, HIV-1, has been reported to form a heterogeneous mixture of tetrameric to dodecameric complexes[19]. In addition to this structural diversity, INs from different genera of retroviruses bind to distinct host co-factors[20,21,22,23], and allosteric IN inhibitors (ALLINs) that target the HIV-1 IN-LEDGF/ p75 interface are being developed as novel antivirals for their capacity to modulate IN multimerization and inhibit late replication steps[24,25,26,27]
We use cryo-electron microscopy, virus infectivity assays, and biochemical analyses to show that phosphatase 2 A (PP2A)-B56γ is an integral component of the HTLV-1 intasome that plays an important role in HTLV-1 infection

Summary

Introduction

Integration of the reverse-transcribed viral DNA into host chromosomes is a critical step in the life-cycle of retroviruses, including an oncogenic delta(δ)-retrovirus human T-cell leukemia virus type-1 (HTLV-1). To address the knowledge gap described above, we determined the structure of the HTLV-1 intasome using cryo-EM and single particle analysis at 3.7-Å resolution We assembled a stable complex including HTLV-1 IN, a fragment of human B56γ spanning residues 11–38029, and a branched DNA molecule containing the viral U5 long terminal repeat (LTR) sequence[30,31] and a target DNA, mimicking the product of the concerted strand-transfer reactions.

Results

Conclusion