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Related Experiment Video

Updated: Jun 25, 2025

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HIV-1 with gag processing defects activates cGAS sensing.

Rebecca P Sumner1,2, Henry Blest3, Meiyin Lin3

  • 1Division of Infection and Immunity, University College London, 90 Gower Street, London, WC1E 6BT, UK. rebecca.sumner@surrey.ac.uk.

Retrovirology
|May 22, 2024
PubMed
Summary
This summary is machine-generated.

Disrupting the HIV-1 capsid with fusion proteins triggers a potent immune response, revealing the capsid's critical role in immune evasion and suggesting new antiviral strategies.

Keywords:
CapsidDNA sensingHIV-1InterferoncGAS

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Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Host pattern recognition receptors detect viruses, inducing type I interferon (IFN) and IFN-stimulated genes (ISGs) to limit viral replication.
  • Human immunodeficiency virus type 1 (HIV-1) is known to poorly activate innate immunity in vitro.
  • The precise function of the HIV-1 capsid in immune evasion remains incompletely understood.

Purpose of the Study:

  • To investigate the role of the HIV-1 capsid in immune system sensing.
  • To determine how modifications to the Gag protein affect innate immune activation.

Main Methods:

  • HIV-1 was produced by co-expressing truncated Gag (capsid amino acids 1-107) fused with luciferase or GFP alongside wild-type Gag-pol.
  • The effect of these modified viral particles on immune responses in THP-1 cells and macrophages was assessed.
  • Mechanisms of innate immune activation, including dependence on reverse transcription and the cGAS DNA sensor, were investigated.

Main Results:

  • Viral particles produced with Gag-fusion proteins induced a potent IFN response, unlike wild-type HIV-1.
  • This innate immune activation was dependent on reverse transcription and the cGAS sensor, indicating viral DNA triggers the response.
  • Gag-fusion incorporation led to defects in wild-type Gag cleavage and reduced TRIM5α restriction, suggesting aberrant particle formation.

Conclusions:

  • The HIV-1 capsid is crucial for evading innate immunity.
  • Disrupting Gag cleavage and capsid formation activates a viral DNA- and cGAS-dependent innate immune response.
  • Capsid-targeting antivirals could enhance innate and adaptive immunity for improved efficacy.