Epigenetic modulation of myeloid cell functions in HIV and SARS-CoV-2 infection

Abstract

Myeloid cells play a vital role in innate immune responses as they recognize and phagocytose pathogens like viruses, present antigens, produce cytokines, recruit other immune cells to combat infections, and contribute to the attenuation of immune responses to restore homeostasis. Signal integration by pathogen recognition receptors enables myeloid cells to adapt their functions by a network of transcription factors and chromatin remodelers. This review provides a brief overview of the subtypes of myeloid cells and the main epigenetic regulation mechanisms. Special focus is placed on the epigenomic alterations in viral nucleic acids of HIV and SARS-CoV-2 along with the epigenetic changes in the host's myeloid cell compartment. These changes are important as they lead to immune suppression and promote the progression of the disease. Finally, we highlight some promising examples of 'epidrugs' that modulate the epigenome of immune cells and could be used as therapeutics for viral infections.

Keywords: AIDS; COVID-19; Epigenetics; HIV; Myeloid cells; SARS-CoV-2.

Fig. 1

Schematic representation of the main layers of epigenetic regulation. Epigenetic modifications include three main categories: A Elevated levels of DNA methylation (hypermethylation) reduce gene expression by inhibiting transcription factor (TF) binding, RNA polymerase activity and promoting a repressive chromatin state in the gene promoter region. Lower levels of DNA methylation (hypomethylation) do not interfere with TF binding and hence are associated with increased gene expression. B Chromatin modifications involve alterations in the structure of chromatin, primarily through histone modifications such as acetylation (H3K9ac, H4K8ac, H3K27ac, etc.) and methylation (H3K4me1, H3K4me3, H3K9me3, H3K27me3, etc.), influencing the accessibility for TF complexes and playing a pivotal role in the regulation of gene expression. These modifications can either promote or inhibit transcription by modulating the interaction between DNA and histone proteins. C Non-coding RNAs (ncRNAs) play a crucial role in epigenetic regulation by participating in processes like histone modification and chromatin remodeling, acting as key mediators in the modulation of gene expression

Fig. 2

Epigenetic changes introduced into the myeloid cell host genome following HIV infection. A HIV infection of myeloid cells induces a chronic inflammatory state as seen in an excessive cytokine production that contributes to increased HIV progression and the development of comorbidities in infected individuals. B Acute HIV infection introduces a differentially hypomethylated DNA signature in isolated monocytes, including genes involved in innate immunity that can only be minimally restored after the onset of cART. C Stimulation with the HIV-1 Tat protein results in the hypermethylation of the miR-124 promoter and downregulation of miR-124 expression in primary microglia cells that correlates with microglial activation and increased release of pro-inflammatory cytokines. D Isolated monocytes from HIV + individuals challenged with M. tuberculosis present a hypomethylated DNA profile that is associated with increased pro-inflammatory cytokine production and impaired pathogen phagocytosis

Fig. 3

Epigenetic regulation of the integrated HIV genome in infected myeloid cells. A In vitro stimulation of a monocytic U38 cell line, which carries the stably integrated HIV-1 promoter, with TLR3 ligands showed an overall decreased HDAC activity and increased HAT activity. As a result, H3K9ac and H4K8ac marks at the HIV promoter were increased, which was shown to correlate with increased promoter activity. B The integrated HIV genome in MDMs presents a unique epigenetic signature composed of the bivalent histone signature H3K9me3, H3K27ac and 5hmC methylation throughout the HIV genome that mediates continuous viral expression. Treatment with a novel purine analogue named nelarabine results in reduced H3K9me3 levels and suppressed viral replication in HIV + macrophages. C HIV-1 infections lead to in vitro upregulation of the host lncRNA HEAL in primary MDMs. Subsequently, HEAL forms a complex with the RNA-binding protein FUS and recruits the HAT p300 to the HIV-1 promoter, resulting in increased H3K27ac levels and HIV expression

Fig. 4

Epigenetic signatures in SARS-CoV-2 pathogenesis. A Variations in the methylation patterns of the ACE2 gene in different cells show a correlation between hypomethylation and increased ACE2R expression in males and individuals with comorbidities in contrast to females and healthy individuals. This suggests a molecular basis for the observed increase of SARS-CoV-2 susceptibility. B After SARS-CoV-2 infection of human lung adenocarcinoma A549 cells, a consistent decrease of the active histone mark H3K27ac and an increase of the repressive histone mark H3K9me3 can be observed, indicating direct infection-related epigenetic changes. C Genome-wide DNA methylation profiles of peripheral blood mononuclear cells from critically COVID-19 patients revealed hypermethylation in regions associated with the IFN response and hypomethylation in regions associated with inflammation and cytokine production

Fig. 5

Viral strategies targeting host epigenetic machinery and translation regulation in SARS-CoV-2. A The NSP5 of SARS-CoV-2 interferes with the epigenetic regulation of the host cell by interacting with HDAC2, leading to inhibition of acetylation degradation and subsequent dysregulated transcription. B NSP14, in complex with NSP10, suppresses host mRNA translation leading to the downregulation of ISGs and consequently inhibited IFN release, and caps the 5′ end of viral RNA to protect viral mRNA and ensure viral replication. C The NSP10 and NSP16 complex adds a methyl group to the viral RNA Cap-1 structure with its 2′-O-methyltransferase activity, helping to camouflage viral RNA from the innate immune system, ensuring RNA stability, and promoting efficient protein production