HIV-1 with gag processing defects activates cGAS sensing

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.