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.
Highlights
In a regulated immune system, macrophages are phagocytic cells that target and break down foreign bodies and regulate lymphocyte activation and recruitment
Macrophage dysregulation in viral pathogenesis is an exploitable space for drug development and should be focused on because it presents a broad target as a pathogenic feature shared by multiple viruses (Figure 1)
Macrophage dysregulation, in the M1 subtype, leads to increased immune activation and inflammation that contributes to viral pathogenesis and development of comorbidities
Summary
In a regulated immune system, macrophages are phagocytic cells that target and break down foreign bodies and regulate lymphocyte activation and recruitment. Macrophage dysregulation results in increased production of pro-inflammatory cytokines leading to accumulation of M1 macrophages and activated immune cells and increased systemic inflammation. Infiltrating neutrophils secrete cytokines (IL-6, IL-12, and IFNg) that contribute to activation of pro-inflammatory macrophages and T helper cell differentiation through Jak STAT signaling [10, 12].
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