Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

Abstract

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

Annexin A1-FPR2/ALX Signaling Axis Regulates Acute Inflammation during Chikungunya Virus Infection

“…Augmented TNF has been implicated in CHIKV-induced chronic arthritis and related to the persistence of pain [ 40 ]. Moreover, CCL2 is involved in cellular infiltration during CHIKV infection [ 6 , 41 ]. At 1 and 3 dpi, a minimal but significant reduction was observed in viral titers in the footpad, quadriceps, spleen, and liver of AnxA1 KO compared with WT (BALB/c) animals ( Figure 3 G).…”

“…Associated with that, neutrophils are known to produce high levels of ROS, which are primarily associated with tissue damage in arbovirus infections such as CHIKV [ 7 , 8 ]. Infected macrophages serve as a possible reservoir for CHIKV and may contribute to the persistent inflammation driven by secretion of cytokines (e.g., IL-6, CCL2) and joint pain associated with infection [ 1 , 41 ]. Furthermore, during the inflammatory response, cytokines mediate the recruitment of neutrophils and monocytes/macrophages that are also involved in the production of direct-acting hyperalgesic mediators, such as PGE 2 , leading to mechanical hypernociception and chronic CHIKV in patients [ 3 , 10 , 47 , 48 ].…”

Phosphatidylcholine Liposomes Down-Modulate CD4 Expression Reducing HIV Entry in Human Type-1 Macrophages

“…Along with CD4 + T lymphocytes, macrophages are the main target of HIV, supporting viral persistence and replication even in subjects undergoing ART or with massive CD4 + T-cell depletion ( 37 ). Macrophages represent a viral reservoir, due to their long life span and resistance to viral cytopathic effect and simultaneously, they are an important vehicle for viral spread for their ubiquitous distribution, including, gut, semen, lung, gut-associated lymphoid tissue, brain, liver, urethra, and lymph nodes ( 37 – 40 ). Macrophages are a heterogeneous cell population, which may range from cells with pro-inflammatory properties and efficient antigen presentation capability, named “classically activated” type-1 macrophages, to cells which are rather involved in the resolution of inflammation, called “alternatively activated” type-2 macrophages ( 41 , 42 ).…”

A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening

“…Indeed, during ART, the HIV genome persists in non-dividing myeloid cells, such as macrophages [35][36][37]. Macrophages are an early cellular target for the HIV-1 infection, and the transmission between humans is caused by the macrophage-tropic virus rather than the CD4+ T cell-tropic virus [38]. In addition, macrophage-tropic HIV-1 is detected during rebound viremia after the discontinuation of ART [39].…”

“…In addition, macrophage-tropic HIV-1 is detected during rebound viremia after the discontinuation of ART [39]. Consequently, new and specific therapeutic targets, such as macrophage-targeting treatments, are required for the radical cure of HIV infection [38].…”