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Translesion DNA Polymerases02:10

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Determining 3'-Termini and Sequences of Nascent Single-Stranded Viral DNA Molecules during HIV-1 Reverse Transcription in Infected Cells
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Structural Basis of Polypurine Track Strand Displacement by HIV-1 Reverse Transcriptase.

Xin Wen1, Rachel Lee1, Sri Dhanya Muppalla2

  • 1Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

Biorxiv : the Preprint Server for Biology
|April 17, 2026
PubMed
Summary
This summary is machine-generated.

HIV-1 reverse transcriptase (RT) uses a unique template flip mechanism to displace polypurine tract (PPT) primers during reverse transcription. This discovery reveals a new vulnerability for designing next-generation antiretrovirals.

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Area of Science:

  • Structural Biology
  • Virology
  • Biochemistry

Background:

  • Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is essential for viral replication.
  • RT must displace polypurine tract (PPT) primers to complete reverse transcription and form viral DNA.
  • The molecular mechanism of PPT strand displacement (SD) by RT was previously unknown.

Purpose of the Study:

  • To elucidate the structural mechanism of PPT strand displacement by HIV-1 RT.
  • To provide the first structural insights into how retroviral polymerases perform PPT SD.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine structures of HIV-1 RT bound to nucleic acid substrates.
  • Biochemical and virological mutagenesis experiments to validate structural findings.

Main Results:

  • First cryo-EM structures of HIV-1 RT with PPT RNA or DNA displacement strands.
  • Identified a novel binding mode involving a 90° template nucleotide flip.
  • Key RT residues (F61, R78, W24) identified at the strand displacement interface.
  • Mutagenesis confirmed essential roles for F61/R78 in polymerization and SD, and W24 exclusively in SD.

Conclusions:

  • The study reveals the molecular mechanism of PPT strand displacement by HIV-1 RT.
  • Identified specific RT-nucleic acid interactions driving PPT SD.
  • These findings highlight a potential mechanistic vulnerability for antiretroviral drug design.