Viral and Cellular Determinants of HIV-1-Induced Innate Immune Activation

Abstract

A fundamental defense mechanism against pathogens is the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). These PRRs are integral components of the innate immune system. This recognition process initiates the interferon (IFN) response mechanism, triggering expression of interferon-stimulated genes (ISGs). Many of these ISGs possess antiviral properties that inhibit viruses, including HIV-1. The PPRs and their following signal pathways vary based on cell type. Publications have shown that an unknown pathway mediated over MAVS is activated by intron-containing RNA from HIV-1 in monocyte-derived macrophages (MDMs). However, the mechanism behind the sensing of the viral genomic RNA is yet unknown.

This work identified two distinct stages of immune recognition in MDMs triggered by HIV-1 infection. The first stage occurred prior to reverse transcription and was influenced by the stability of the viral capsid. In the second stage, characterized by a more robust immune response, a short peptide sequence encoded by the N-terminus of gag was crucial to inducing inflammatory responses. While partially spliced or full-length viral RNA in the cytoplasm was required for Gag protein translation, the myristoylation site of Gag was essential to induce innate sensing in MDMs. Furthermore, we examined whether THP-1 or U937 cells in differentiated state showed a similar phenotype to MDMs during HIV-1 infection to identify the molecular mechanisms involved in sensing the virus. We found that U937 cells exhibited robust innate response at a late-stage of virus replication, whereas pre-integration determinants, observed in MDMs, differ. Surprisingly, THP-1 cells exhibited minimal innate immune responses against HIV-1 and showed significant differences from the responses observed in MDMs and U937 cells. Our findings reveal that HIV-1 sensing in differentiated THP-1 and U937 cells does not parallel the responses seen in primary cells. These results enable new research targets in regard to find the cellular sensor, which induces HIV-1 chronic inflammation in MDMs and highlight the importance of research in primary cell systems.