Phospholipases: at the crossroads of the immune system and the pathogenesis of HIV-1 infection

Abstract

Multiple host factors and their interactions with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. The virus exploits the cell-signaling networks to prepare the ground for viral replication, to affect functions of either infected or uninfected bystander cells, and to evade the immune response. These events are hallmarks of HIV-1 pathogenesis that lead toward AIDS. Phospholipases are essential mediators of intracellular and intercellular signaling. They function as phospholipid-hydrolyzing enzymes, generating many bioactive lipid mediators or second messengers, which control multiple cellular functions, thus regulating a variety of physiologic and pathophysiologic processes. These enzymes also represent important components of the cell-signaling networks exploited by HIV-1 and its proteins to favor viral replication and persistence, as well as immune response dysfunction. Although some individual phospholipases were studied in the context of HIV-1 infection, the mechanisms whereby they regulate diverse infection-associated processes, as well as the interaction among different phospholipases have yet to be fully elucidated. In this review, we discuss the principal aspects of the complex interaction between phospholipases, HIV-1, and the immune system. A thorough understanding of the signaling networks that involve phospholipases in both HIV-1-infected cells and individuals is essential to determine whether therapeutic targeting of these enzymes may represent a novel approach to control viral replication, as well as the associated inflammation and comorbidities.

Macrophages and Phospholipases at the Intersection between Inflammation and the Pathogenesis of HIV-1 Infection

“…PLs hydrolyze phospholipids into fatty acids (FAs) and other lipophilic substances. They are classified into four distinct families, named PLA, PLB, PLC and PLD, based on the stereospecifically numbered sites within phospholipids where they promote cleavage (for and extensive review see [ 12 ]). Phospholipid hydrolysis is a widespread response triggered by most cytokines, growth factors, neurotransmitters, hormones, and other extracellular signals, and its products include many of the most important second messengers, such as inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), that are implicated in cellular responses.…”

“…Several signal transduction pathways are involved in monocyte/macrophage activation by HIV-1 as well as microbial products, such as LPS [ 10 , 11 ]. Among these pathways, phospholipase (PL) signaling is increasingly recognized to be essential in the orchestration of the inflammatory response [ 12 ]. These enzymes catalyze phospholipid cleavage, leading to the production of lipid mediators or second messengers that have central roles in signal transduction.…”

Fruit Bagasse Phytochemicals from Malpighia Emarginata Rich in Enzymatic Inhibitor with Modulatory Action on Hemostatic Processes

“…Such mediators are responsible for changes in hemostasis (Nanda et al., ), and are involved in a series of diseases such as asthma and allergic reactions (Pniewska et al., ), arthritis (Kokotos et al., ), atherosclerosis (Ait‐Oufella, Mallat, & Tedgui, ), cancer (Berg, Gelb, Tsai, & Jain, ), neurological disorders—as Alzheimer's (Sagy‐Bross et al., ), multiple sclerosis (Kalyvas and David, ), and Parkinson's disease (Lee, Bazinet, Rapoport, & Bhattacharjee, ). Therefore, these enzymes can act as essential mediators of intracellular and intercellular signaling, hydrolyzing phospholipids and generating bioactive lipid mediators or messengers that control multiple cell functions and regulate a physiological and pathophysiological processes (Cechetti, Spadaro, Gessani, Podo, & Fantuzzi, ; Masud et al., ; Ramanadtham et al., ). Several plant extracts have been described with inhibitory activity on phospholipases A 2 and being efficient in inhibiting or preventing inflammatory processes, aiding in the management of inflammatory diseases (Kishore et al., ; Kuganesan et al., ; Moura et al., ; Silva et al., ).…”

“…. hydrolyzing phospholipids and generating bioactive lipid mediators or messengers that control multiple cell functions and regulate a physiological and pathophysiological processes (Cechetti, Spadaro, Gessani, Podo, & Fantuzzi, 2017;Masud et al, 2005;Ramanadtham et al, 2004). Several plant extracts have been described with inhibitory activity on phospholipases A 2 and being efficient in inhibiting or preventing inflammatory processes, aiding in the management of inflammatory diseases (Kishore et al, 2016;Kuganesan et al, 2017;Moura et al, 2017;Silva et al, 2016).…”

Jabuticaba (Plinia jaboticaba) skin extracts as inhibitors of phospholipases A2 and proteases

“…Phospholipases A 2 are considered as important regulators of the arachidonic acid pathway and can act as essential mediators of intracellular and intercellular signaling, hydrolyzing phospholipids and generating bioactive lipid mediators or messengers that control multiple cell functions and regulate physiological and pathophysiological processes (Ramanadham et al 2004, Masuda et al 2005, Cechetti et al 2017. While the proteases act selectively in the factors of the coagulation cascade, with effect on platelet aggregation, fibrinolysis and coagulation (Braud and Wisner 2000).…”