Abstract
A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation. Macrophages play a protagonist role in this context since they are persistently infected while being a major effector of the innate immune response through the generation of type-I interferons (type I IFN) and IFN-stimulated genes (ISGs). The balance in the IFN signaling and the ISG induction is critical to promote a successful HIV-1 infection. Classically, the IFNs response is fine-tuned by opposing promotive and suppressive signals. In this context, it was described that HIV-1-infected macrophages can also synthesize some antiviral effector ISGs and, positive and negative regulators of the IFN/ISG signaling. Recently, epitranscriptomic regulatory mechanisms were described, being the N6-methylation (m6A) modification on mRNAs one of the most relevant. The epitranscriptomic regulation can affect not only IFN/ISG signaling, but also type I IFN expression, and viral fitness through modifications to HIV-1 RNA. Thus, the establishment of replication-competent latent HIV-1 infected macrophages may be due to non-classical mechanisms of type I IFN that modulate the activation of the IFN/ISG signaling network.
Highlights
A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation
HIV-1 entry into the central nervous system (CNS) leads to neurological abnormalities, termed HIV-associated neurocognitive disorders (HAND), which manifests despite successful antiretroviral therapy (ART) in 30% of cases [17]
They concluded that latently HIV-1-infected macrophages/microglia, which act as HIV-1 reservoirs, block a very early step of apoptosis that involves the accumulation of Bim protein
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. HIV-1 entry into the CNS leads to neurological abnormalities, termed HIV-associated neurocognitive disorders (HAND), which manifests despite successful ART in 30% of cases [17] Viral proteins such as Tat and gp120, together with the expression of cytokines/chemokines and the activation of adhesion molecules, drive the additional recruitment of monocytes and lymphocytes, leading to chronic neuroinflammation that is conducive to the production of neurotoxic factors and, eventually, neuronal dysfunction and cell death [4,18,19,20]. In CD4+ HIV-1-infected cells, the transcription factor hypoxia-inducible factor 1 (HIF-1) promotes viral replication and inflammation by promoting the release of extracellular vesicles This triggers the secretion of inflammatory mediators, resulting in the secretion of IFN-γ by bystander. CD4+ T cells and IL-1 and IL-6 by bystander macrophages, contributing to HIV-1 pathogenesis [21]
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