Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications

Abstract

Although antiretroviral therapy (ART) has dramatically improved the outlook of the HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive therapy are still at higher risk for a range of comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation and immune activation are thought to be an underlying cause of these comorbidities. Many of the factors thought to drive chronic inflammation and immune activation in HIV overlap with factors known to induce trained immunity. Trained immunity is a form of innate immune memory that metabolically and epigenetically reprograms innate immune cells to mount enhanced inflammatory responses upon secondary encounter with unrelated inflammatory stimuli. While this phenotype has been characterized in a variety of disease states in animals and humans, very little is known about its potential contribution to chronic HIV pathogenesis. In this review, a broad overview of innate immune memory in the periphery and the central nervous system (CNS) is provided and the evidence for trained immunity in the context of HIV is considered. In PLWH on ART, this phenotype could contribute to the chronic inflammation and immune activation associated with HIV comorbidities and could complicate HIV cure strategies due to the potential persistence of the phenotype after eradication of the virus. Further research into this immune state in the context of HIV may open the door for new therapeutics aimed at treating HIV comorbidities like HAND.

Keywords: Cytokines; HIV-associated neurocognitive disorders; Innate immune memory; Microglia; Monocytes; Neuroinflammation.

Fig. 1

Proposed model for the induction of trained immunity in PLWH on ART and potential clinical implications of this phenomenon. a) known inducers of trained immunity that have been shown to be circulating at levels higher than normal in PLWH on ART as well as factors in PLWH on ART that have not yet been confirmed as trained immunity inducers, but which studies have shown to cause phenotypes analogous to trained immunity. b) the compartments and cell types that would be affected by these known and potential inducers of trained immunity circulating in PLWH on ART and how interactions between these compartments could perpetuate trained immunity phenotypes. c) the putative outcomes of persistent trained immunity phenotypes and their potential clinical implications