Host T Cell Dedifferentiation Effects Drive HIV-1 Latency Stability

Area of Science:

• Immunology
• Virology
• Genomics

Background:

• HIV-1 latency is a major barrier to cure, complicated by heterogeneity in infected cells.
• Understanding the biomolecular mechanisms of HIV-1 latency is crucial for developing effective therapies.
• Previous studies highlighted significant heterogeneity in latently infected primary T cells.

Purpose of the Study:

• To investigate the mechanisms of inter-cell heterogeneity in latently HIV-1-infected T cells.
• To identify the biomolecular phenotype of latently HIV-1-infected cells.
• To explore therapeutic strategies targeting the host cell phenotype to eliminate HIV-1 latency.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) was used to analyze gene expression profiles of latently infected T cell lines and primary T cells.
• Transcriptomic heterogeneity was assessed to understand inter-cell variations.
• Data mining of patient-derived scRNA-seq data was performed to identify common dedifferentiation motifs.

Main Results:

• Latently HIV-1-infected T cells exhibit a dedifferentiated phenotype, losing T cell markers and adopting profiles similar to hematopoietic stem cells (HSC).
• This dedifferentiation leads to functional changes, including efficient suppression of superinfections and a shift towards glycolysis.
• Metabolic reprogramming or redifferentiation of these cells destabilized the latent HIV-1 infection.
• Analysis of patient data confirmed similar dedifferentiation patterns, with over 20% of differentially regulated genes linked to hematopoietic lineage development.

Conclusions:

• Latent HIV-1 infection is a host cell phenomenon characterized by T cell dedifferentiation.
• Therapeutic strategies should focus on restoring normal host cell functionality to reactivate latent HIV-1.
• Targeting the dedifferentiated phenotype of latently infected cells offers a promising approach for HIV-1 cure interventions.