Transcriptomic Signatures of Immune Suppression and Cellular Dysfunction Distinguish Latent from Transcriptionally Active HIV-1 Infection in Dendritic Cells

TL;DR

This study shows how HIV-1 infection in dendritic cells differs between active and latent states, affecting immune responses and cell function.

Contribution

The study identifies distinct transcriptomic signatures distinguishing active and latent HIV-1 infection in dendritic cells.

Findings

Active HIV-1 infection is linked to cellular stress and RNA processing, while suppressing antigen presentation.

Latent HIV-1 infection is associated with a hyporesponsive state with downregulated interferon and metabolic pathways.

Transcriptionally active HIV-1 correlates with a metabolically strained but immunologically engaged state in dendritic cells.

Abstract

Dendritic cells (DCs) are essential for antiviral immunity but are also susceptible to HIV-1 infection. Although sensing and restriction pathways in DCs are well described, the mechanisms underlying latent infection and its functional consequences remain unclear. In this study, we performed transcriptomic profiling of monocyte-derived DCs harboring transcriptionally active (Active-HIV) or latent HIV-1 (Latent-HIV) proviruses using a dual-reporter virus. Gene set enrichment analysis revealed suppression of metabolic and stress-modulatory programs in Active-HIV compared to unexposed DCs. In contrast, Latent-HIV showed broad downregulation of pathways, including interferon and innate responses and metabolic programs, indicating a hyporesponsive and dampened antiviral state despite the absence of differentially expressed genes (DEGs). DEG analysis of Active-HIV versus Latent-HIV showed that active transcription associates with cellular stress, cytoskeletal remodeling, and RNA processing. Functional analyses further demonstrated the activation of RNA processes, the suppression of antigen-presentation pathways, and altered membrane and cytoskeletal signaling in Active-HIV. These pathways suggest that transcriptionally active HIV-1 is linked to cellular programs supporting replication, coinciding with a metabolically strained yet immunologically engaged state that may impair antigen presentation. Conversely, latently infected DCs display a hyporesponsive state consistent with proviral silencing. This dichotomy reveals distinct mechanisms of DC dysfunction that may facilitate HIV-1 persistence and immune evasion.

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