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 represent a hyperlink in between innate and adaptive immunity [1,2]. Although constituting only 0.2.eight of human blood cells, they have garnered interest simply because they are able to generate as much as 1000-fold extra sort I interferon (IFN) (specifically IFN-) than any other cell varieties [3]. Distinctive studies have shown that pDCs are involved in sophisticated inflammatory response in a number of autoimmune diseases and infections, including Human Immunodeficiency Virus (HIV) [4]. In accordance with what was observed inside a SIV (Simian Immunodeficiency Virus)-macaque model, pDCs will be the very first predominant cell variety to arrive to infected mucosal web pages exactly where the infection is generally acquired [7]. Even though they don’t represent among the list of most important reservoirs of the virus (including macrophages or CD4+Copyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is definitely an open access short article distributed below the terms and situations of the Creative 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,two ofT lymphocytes), they’re able to be infected as they express CD4 receptor as well as the co-receptors CXCR4 and CCR5, the surface molecules which can be targeted by the virus [81]. It has been reported that pDCs may possibly contribute dichotomously to both chronic immune activation and immunosuppression [12,13]. Over the years, the accessory NK1 Agonist Formulation protein Nef has been identified as one of many important determinants of HIV pathogenicity [14]. HIV-1 Nef (274 kDa, in accordance with the MMP-7 Inhibitor Purity & Documentation isolate type) is actually a myristoylated, cytoplasmic multifunctional protein, partially connected with all the cell membrane, that acts as a molecular adaptor inside the cells, exerting its effects via precise 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 with 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 very first time in HIV-infected macrophages by the Mario Stevenson laboratory [17]. Preceding research performed in our lab also demonstrated that the recombinant myristoylated Nef protein (myrNefSF2) was swiftly internalized in key 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 particular STAT-1, -2 and -3 [18,202]. Considerably evidence also points to the capacity of Nef to exploit the vesicular trafficking machinery from the host as a “Trojan horse” to become transferred via extracellular vesicles (EVs) and nanotubes from 1 cell to a further, hence escaping the immune program and exerting its effects on both infected and uninfected cells [235]. EVs, like exosomes (30-150 nm diameter), formed as intraluminal vesicles (ILVs) in mul.
