Cells; HIV-1 Nef; cytokines; extracellular vesicles1. Introduction Plasmacytoid dendritic cells (pDCs) are one of the two principal subsets of human dendritic cells (DCs) and PARP1 Activator Accession represent a link involving innate and adaptive immunity [1,2]. Even though constituting only 0.2.eight of human blood cells, they have garnered interest due to the fact they may be in a position to make as much as 1000-fold much more variety I interferon (IFN) (especially IFN-) than any other cell forms [3]. Different research have shown that pDCs are involved in advanced inflammatory response in various autoimmune diseases and infections, which includes Human Immunodeficiency Virus (HIV) [4]. As outlined by what was observed within a SIV (Simian Immunodeficiency Virus)-macaque model, pDCs would be the initial predominant cell kind to arrive to infected mucosal web sites where the infection is typically acquired [7]. Although they do not represent among the key reservoirs of the virus (which include PI3Kδ Inhibitor custom synthesis macrophages or CD4+Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access write-up distributed under the terms and situations of the Inventive Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ four.0/).Viruses 2022, 14, 74. https://doi.org/10.3390/vhttps://www.mdpi.com/journal/virusesViruses 2022, 14,2 ofT lymphocytes), they are able to be infected as they express CD4 receptor along with the co-receptors CXCR4 and CCR5, the surface molecules which are targeted by the virus [81]. It has been reported that pDCs may contribute dichotomously to each chronic immune activation and immunosuppression [12,13]. More than the years, the accessory protein Nef has been identified as among the main determinants of HIV pathogenicity [14]. HIV-1 Nef (274 kDa, based on the isolate form) is actually a myristoylated, cytoplasmic multifunctional protein, partially linked together with the cell membrane, that acts as a molecular adaptor inside the cells, exerting its effects via specific protein rotein interaction motifs [15,16]. Among the multiple functions ascribed to Nef, the hijacking of cellular signalling pathways and membrane trafficking have garnered the interest from the scientific neighborhood. Nef regulation of cellular signalling and trafficking pathways strongly suggests that it could influence per se the cytokine/chemokine network, possibly contributing to chronic inflammation, as observed for the first time in HIV-infected macrophages by the Mario Stevenson laboratory [17]. Prior studies performed in our lab also demonstrated that the recombinant myristoylated Nef protein (myrNefSF2) was quickly internalized in primary monocyte-derived macrophages (MDMs) and triggered NF-B, MAPKs (Mitogen-Activated Protein Kinase) and IRF-3 (Interferon Regulatory Aspect three) activation, inducing the production and release of a set of cytokines/chemokines (CCL2/MIP1 and CCL4/MIP-1, but in addition IL-6, TNF-, IL-1 and IFN) [18,19]. The latter, in turn, activated some signal transducers and activators of transcription (STAT) molecules in an autocrine and/or paracrine manner, in distinct STAT-1, -2 and -3 [18,202]. A great deal evidence also points towards the potential of Nef to exploit the vesicular trafficking machinery with the host as a “Trojan horse” to become transferred via extracellular vesicles (EVs) and nanotubes from one cell to a different, as a result escaping the immune method and exerting its effects on each infected and uninfected cells [235]. EVs, like exosomes (30-150 nm diameter), formed as intraluminal vesicles (ILVs) in mul.