Cells; HIV-1 Nef; cytokines; extracellular vesicles1. Introduction Plasmacytoid dendritic cells (pDCs) are on the list of two principal subsets of human dendritic cells (DCs) and represent a hyperlink among innate and adaptive immunity [1,2]. Though constituting only 0.two.eight of human blood cells, they have garnered interest due to the fact they are able to produce up to 1000-fold a lot more variety I interferon (IFN) (particularly IFN-) than any other cell types [3]. Distinct research have shown that pDCs are involved in advanced inflammatory response in quite a few autoimmune diseases and infections, which includes Human Immunodeficiency Virus (HIV) [4]. According to what was observed inside a SIV (Simian Immunodeficiency Virus)-macaque model, pDCs are the first predominant cell variety to arrive to infected mucosal web pages exactly where the infection is frequently acquired [7]. While they don’t represent one of several key reservoirs from the virus (for example macrophages or CD4+Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is definitely an open access short article distributed beneath the terms and situations from the Inventive Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).Viruses 2022, 14, 74. https://doi.org/10.3390/vhttps://www.mdpi.com/journal/virusesViruses 2022, 14,2 ofT lymphocytes), they could be infected as they express CD4 receptor along with the co-receptors CXCR4 and CCR5, the surface molecules that are targeted by the virus [81]. It has been reported that pDCs could contribute dichotomously to each chronic immune activation and immunosuppression [12,13]. Over the years, the accessory protein Nef has been identified as among the big determinants of HIV pathogenicity [14]. HIV-1 Nef (274 kDa, as outlined by the isolate variety) is actually a myristoylated, cytoplasmic multifunctional protein, partially linked using the cell membrane, that acts as a molecular adaptor inside the cells, exerting its effects via Activated Leukocyte Cell Adhesion Molecule (ALCAM) Proteins Species precise protein rotein interaction motifs [15,16]. Amongst the various functions ascribed to Nef, the hijacking of cellular signalling pathways and membrane trafficking have garnered the interest on the scientific neighborhood. Nef regulation of cellular signalling and trafficking pathways strongly suggests that it could influence per se the cytokine/chemokine network, possibly IL-15R alpha Proteins Formulation contributing to chronic inflammation, as observed for the first time in HIV-infected macrophages by the Mario Stevenson laboratory [17]. Earlier research carried out in our lab also demonstrated that the recombinant myristoylated Nef protein (myrNefSF2) was rapidly internalized in primary monocyte-derived macrophages (MDMs) and triggered NF-B, MAPKs (Mitogen-Activated Protein Kinase) and IRF-3 (Interferon Regulatory Element three) activation, inducing the production and release of a set of cytokines/chemokines (CCL2/MIP1 and CCL4/MIP-1, but additionally 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 specific STAT-1, -2 and -3 [18,202]. A lot evidence also points for the ability of Nef to exploit the vesicular trafficking machinery in the host as a “Trojan horse” to be transferred via extracellular vesicles (EVs) and nanotubes from one particular cell to a different, therefore escaping the immune method and exerting its effects on each infected and uninfected cells [235]. EVs, such as exosomes (30-150 nm diameter), formed as intraluminal vesicles (ILVs) in mul.
