With successful antiretroviral therapy, HIV-1-infected subjects can achieve undetectable peripheral viral loads and immune homeostasis. However, in a subset of individuals on therapy, peripheral monocytes have a gene expression profile characteristic of a type 1 interferon α (IFN) response. This type 1 IFN response correlates with a number of pathogenic conditions including neural cell injury and in combination with HCV infection, cognitive impairment. Lessons from the non-human primate models of pathogenic and nonpathogenic SIV suggest that returning the initial IFN spike in acute SIV infection to normal allows the immune system to control infection and return to homeostasis. An IFN "alarm" signature, defined as monocyte activation with overexpression of the type1 IFN genes IFI27 and CD169, would be useful for identifying a subset of subjects with HIV-1 infection that could progress to a number of pathologies associated with immune activation including cognitive dysfunction. This strategy is being actively pursued for autoimmune diseases that are characterized by an IFN signature. Therapies to block the IFN signature are under investigation as a means to reset the immune system and in a subset of HIV-1-infected subjects may be an adjuvant to standard antiviral therapy to return cognitive function.

Extracellular vesicles classified as exosomes, microvesicles, or apoptotic bodies based on size are shed from most cells under normal as well as pathological conditions. They are released into the surrounding milieu, including plasma, urine, saliva, and tissues. Exosomes are highly enriched in microRNAs (miRs), which function in recipient cells by regulating posttranscriptional processing of targeted genes. Interaction of a miR with its mRNA target typically results in suppression of its gene expression. Peripheral inflammatory conditions can modulate miR expression in immune cells such as circulating monocytes that can influence their migration and differentiation. Changes within monocyte-derived macrophage miR expression can influence exosome content and further affect end-organ target cells.

Atherosclerosis is an inflammatory disease that is accelerated in human immunodeficiency virus (HIV) infection. Individuals with HIV infection have an activated type I interferon (IFN) monocyte phenotype, which may enhance uptake of modified low-density lipoprotein (LDL) thereby initiating a prefoam cell pathology and recruitment into atherosclerotic plaques. In a sampling of HIV-infected subjects, an increase in monocyte activation genes, MX1 and CXCL10, correlated with monocyte expression of the scavenger receptor A (SR-A), a major receptor for lipid uptake and foam cell formation. Monocytes from HIV-infected subjects accumulated more lipid than control uninfected subjects. We modeled increased activation in HIV infection by priming human monocytes with IFNα followed by exposure to acetylated LDL (acLDL). Exposure to IFNα increased acLDL uptake, which generated increased cellular reactive oxygen species (ROS). We posit that HIV infection augments formation of arterial plaques by triggering monocyte activation with a type I IFN profile, which induces SR-A expression, lipid uptake, and subsequent ROS production. These findings may explain in part why HIV-infected individuals with chronic immune activation have an increased risk of atherosclerosis.

Background

Individuals infected with both HIV and hepatitis C virus (HCV) have shown impaired performance on different neuropsychological (NP) tests; however, whether coinfected individuals with controlled HIV and minimal liver damage in the era of antiretroviral therapy have impairment is understudied.

Methods

Nineteen HCV monoinfected, 17 HIV/HCV coinfected, and 17 control male participants were evaluated for depression, attention, executive function, information processing, fine motor speed, and verbal/visual learning/memory. Eleven controls and 14 HIV monoinfected participants with controlled viral load from a previous study were also included for comparison. At time of testing, participants were not using drugs or alcohol and did not have cirrhosis. A global deficit score (GDS) was calculated from 7 domains of NP tests and alterations in specific domains were determined.

Results

HIV/HCV subjects had a higher depression score (11.1 ± 7.5) than controls (5.4 ± 4.1, P = 0.010) and a higher GDS score (0.77 ± 0.47) than HCV (0.46 ± 0.34, P = 0.036), HIV (0.45 ± 0.36, P = 0.008), and controls (0.30 ± 0.29, P = 0.001). Coinfection was associated with worse scores in attention working memory (P =0.007), executive function (P = 0.01), fine motor function (P = 0.011), verbal learning/memory (P < 0.001), and visual learning/memory (P < 0.001) compared to controls. Within the HCV group, viral load was associated with lower attention, executive function, and information processing speed and positively with GDS.

Conclusions

Coinfection significantly increased the risk of cognitive impairment in subjects with controlled HIV viral loads. In HCV monoinfected but not coinfected subjects, HCV viral load correlated with worsening GDS, suggesting different pathways for NP impairment.

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD− controls) and 18 women (10 PTSD+ and 8 age-matched PTSD− controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with q-PCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD.

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associatedalterations in inflammatory activity may contribute to thisincreased risk. However, little is known about convergent SNS, HPAand inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined theprevalence of specific transcription factor binding motifsin the promoter regions of differentially expressed genes in monocytesfrom individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls)and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel familyof transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors,which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveysglucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κBand non-significant down-regulation of target genes for GR,but significant down-regulation of target genes for CREB/ATF.Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

Background

HIV-1 infection dysregulates the immune system and alters gene expression in circulating monocytes. Differential gene expression analysis of CD14(+) monocytes from subjects infected with HIV-1 revealed increased expression of sialoadhesin (Sn, CD169, Siglec 1), a cell adhesion molecule first described in a subset of macrophages activated in chronic inflammatory diseases.

Methodology/principal findings

We analyzed sialoadhesin expression on CD14(+) monocytes by flow cytometry and found significantly higher expression in subjects with elevated viral loads compared to subjects with undetectable viral loads. In cultured CD14(+) monocytes isolated from healthy individuals, sialoadhesin expression was induced by interferon-alpha and interferon-gamma but not tumor necrosis factor-alpha. Using a stringent binding assay, sialoadhesin-expressing monocytes adsorbed HIV-1 through interaction with the sialic acid residues on the viral envelope glycoprotein gp120. Furthermore, monocytes expressing sialoadhesin facilitated HIV-1 trans infection of permissive cells, which occurred in the absence of monocyte self-infection.

Conclusions/significance

Increased sialoadhesin expression on CD14(+) monocytes occurred in response to HIV-1 infection with maximum expression associated with high viral load. We show that interferons induce sialoadhesin in primary CD14(+) monocytes, which is consistent with an antiviral response during viremia. Our findings suggest that circulating sialoadhesin-expressing monocytes are capable of binding HIV-1 and effectively delivering virus to target cells thereby enhancing the distribution of HIV-1. Sialoadhesin could disseminate HIV-1 to viral reservoirs during monocyte immunosurveillance or migration to sites of inflammation and then facilitate HIV-1 infection of permissive cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects' GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.