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

Abstract

Persistent low grade immune activation and chronic inflammation are nowadays considered main driving forces of the progressive immunologic failure in effective antiretroviral therapy treated HIV-1 infected individuals. Among the factors contributing to this phenomenon, microbial translocation has emerged as a key driver of persistent immune activation. Indeed, the rapid depletion of gastrointestinal CD4+ T lymphocytes occurring during the early phases of infection leads to a deterioration of the gut epithelium followed by the translocation of microbial products into the systemic circulation and the subsequent activation of innate immunity. In this context, monocytes/macrophages are increasingly recognized as an important source of inflammation, linked to HIV-1 disease progression and to non-AIDS complications, such as cardiovascular disease and neurocognitive decline, which are currently main challenges in treated patients. Lipid signaling plays a central role in modulating monocyte/macrophage activation, immune functions and inflammatory responses. Phospholipase-mediated phospholipid hydrolysis leads to the production of lipid mediators or second messengers that affect signal transduction, thus regulating a variety of physiologic and pathophysiologic processes. In this review, we discuss the contribution of phospholipases to monocyte/macrophage activation in the context of HIV-1 infection, focusing on their involvement in virus-associated chronic inflammation and co-morbidities.

The gut microbiota and its interactions with cardiovascular disease

“…Intestinal Streptococci were implicated in the onset of Kawasaki disease, although the precise aetiology remains unclear (Kinumaki, et al , ). Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) inflict gut mucosal damage, leading to microbial translocation and persistent low‐grade chronic inflammation associated with the contribution of phospholipase to monocyte or macrophage activation, and these effects subsequently result in cardiovascular comorbidities (Kristoff, et al , ; Spadaro, et al , ) (Fig. ).…”

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…There is mounting evidence that chronic HIV-1 disease progression is characterized by systemic immune activation and oxidative stress, which can occur even while viremia is controlled with antiretrovirals (158)(159)(160). This systemic inflammation is thought to be caused by a number of factors; namely gut permeability, activated monocytes and cytokine derangement (160)(161)(162)(163). High levels of viremia are accompanied by high levels of IFN-γ, TNF-α, IFNα, and other inflammatory markers (164)(165)(166).…”

β-Catenin and TCFs/LEF signaling discordantly regulate IL-6 expression in astrocytes

“…Inflammation in the Central Nervous System (CNS) is orchestrated by numerous biological factors; among these is the pleiotropic cytokine IL-6. Elevated levels of IL-6 is associated with neuroinflammation/neurodegenerative diseases such as Alzheimer's (AD) [1][2][3][4], Multiple Sclerosis (MS) [5,6], Parkinson's Disease (PD) [7,8], Huntington's Disease (HD) [9,10], and HIV-Associated Neurocognitive Disorders (HAND) [11][12][13] as well as psychiatric disorders such as major depression [14][15][16] and schizophrenia [17][18][19]. Most resident CNS cells secrete IL-6, including astrocytes, neurons, microglia, and endothelial cells [20,21].…”

“…To add to the complex signaling behavior of IL-6, in MS IL-6 induces proliferation and differentiation of T cells into the CNS by upregulating V-CAM1 [5,6]. Similarly in HAND higher IL-6 levels are associated with neuronal damage and/or death [11][12][13]. However in AD, although IL-6 is found to be in areas of beta-amyloid [1][2][3][4], it has also been found to have a beneficial role by reducing beta-amyloid deposition and inducing plaque clearance [24].…”