Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• Human immunodeficiency virus type 1 (HIV-1) integration into host DNA is crucial for viral replication.
• The biological significance of HIV-1's preferential integration into transcribed genes remains unclear.
• Understanding integration site selection is key to developing novel antiviral strategies.

Purpose of the Study:

• To investigate the mechanism behind HIV-1 integration site selection.
• To identify host factors that influence HIV-1 infection and integration.
• To explore the potential of digoxin as an antiviral agent targeting HIV-1.

Main Methods:

• High-throughput chemical screening to identify inhibitors of HIV-1 infection.
• RNA sequencing (RNAseq) and integration mapping to analyze viral and host gene expression.
• Analysis of over 400,000 unique integration sites.
• Use of neutralizing antibodies to block specific cellular pathways.

Main Results:

• Digoxin potently inhibits wild-type HIV-1 infection, with greater efficacy than against a specific capsid mutant (N74D).
• Digoxin represses viral gene expression by targeting the cellular Na+/K+ ATPase and down-regulating T-cell activation and metabolism genes (CD40L, CD38).
• HIV-1 preferentially integrates into genes susceptible to digoxin-mediated repression, particularly those involved in T-cell activation and metabolism.

Conclusions:

• Digoxin's selective inhibition of HIV-1 relies on both integration site targeting and the repression of specific host gene networks.
• HIV-1 integration site selection is functionally linked to T-cell activation status.
• HIV-1 may have evolved integration preferences to modulate its early gene expression with the host cell's activation state, influencing viral latency and reactivation.