Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia.

BACKGROUND: Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia. METHODS: Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from the cohort. Their association with proinflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models. RESULTS: High levels of sgp120 and anti-cluster A antibodies were inversely correlated with CD4+ T cell count and CD4/CD8 ratio. The presence of sgp120 was associated with increased levels of interleukin 6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques. CONCLUSIONS: This study showed that sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of people living with HIV, contributing to the development of premature comorbid conditions.

Association Between the Development of Subclinical Cardiovascular Disease and Human Immunodeficiency Virus (HIV) Reservoir Markers in People With HIV on Suppressive Antiretroviral Therapy.

We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation.

Information processing varies between insomnia types: measures of N1 and P2 during the night.

This study compared cortical arousal mechanisms during the night using event-related potentials (N1 and P2), and compared sleep misperception in 30 adults with psychophysiological insomnia (Psy-I), 28 adults with paradoxical insomnia (Para-I), and 30 good sleepers (GS). Participants (age range = 25-55 years) spent 4 consecutive nights in the laboratory, and Night-4 data were used for analysis. N1 amplitude was generally larger in both insomnia groups compared to GS, and P2 amplitude was larger in Para-I than in the 2 other groups, especially in REM sleep. Results suggest that, although hyperarousal appears to persist during sleep in adults with insomnia, inhibition deficits are more likely to be present in Para-I compared to Psy-I.

Plasmatic HIV-1 soluble gp120 is associated with immune dysfunction and inflammation in ART-treated individuals with undetectable viremia.

Background: Chronic inflammation persists in some people living with HIV (PLWH), even during antiretroviral therapy (ART) and is associated with premature aging. The gp120 subunit of the HIV-1 envelope glycoprotein can shed from viral and cellular membranes and can be detected in plasma and tissues, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, which were previously linked to CD4 depletion in vitro , could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. Methods: Cross-sectional assessment of plasmatic sgp120 and anti-cluster A antibodies was performed in 386 individuals from CHACS. Their association with pro-inflammatory cytokines, as well as subclinical coronary artery disease measured by computed tomography coronary angiography was assessed using linear regression models. Results: In individuals with high levels of sgp120, anti-cluster A antibodies inversely correlated with CD4 count (p=0.042) and CD4:CD8 ratio (p=0.004). The presence of sgp120 was associated with increased plasma levels of IL-6. In participants with detectable atherosclerotic plaque and detectable sgp120, sgp120 levels, anti-cluster A antibodies and their combination correlated positively with the total volume of atherosclerotic plaques (p=0.01, 0.018 and 0.006, respectively). Conclusion: Soluble gp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities. Whether drugs targeting sgp120 could mitigate HIV-associated comorbidities in PLWH with suppressed viremia warrants further studies. Key points: Soluble gp120 is detected in the plasma of people living with HIV-1 with undetectable viremia. The presence of soluble gp120 and anti-cluster A antibodies is associated with immune dysfunction, chronic inflammation, and sub-clinical cardiovascular disease.

Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis.

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, ß, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1ß and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1ß in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.

Persistent expansion and Th1-like skewing of HIV-specific circulating T follicular helper cells during antiretroviral therapy.

BACKGROUND: Untreated HIV infection leads to alterations in HIV-specific CD4+ T cells including increased expression of co-inhibitory receptors (IRs) and skewing toward a T follicular helper cell (Tfh) signature. However, which changes are maintained after suppression of viral replication with antiretroviral therapy (ART) is poorly known. METHODS: We analyzed blood CD4+ T cells specific to HIV and comparative viral antigens in ART-treated people using a cytokine-independent activation-induced marker assay alone or in combination with functional readouts. FINDINGS: In intra-individual comparisons, HIV-specific CD4+ T cells were characterized by a larger fraction of circulating Tfh (cTfh) cells than CMV- and HBV-specific cells and preferentially expressed multiple IRs and showed elevated production of the Tfh cytokines CXCL13 and IL-21. In addition, HIV-specific cTfh exhibited a predominant Th1-like phenotype and function when compared to cTfh of other specificities, contrasting with a reduction in Th1-functions in HIV-specific non-cTfh. Using longitudinal samples, we demonstrate that this distinct HIV-specific cTfh profile was induced during chronic untreated HIV infection, persisted on ART and correlated with the translation-competent HIV reservoir but not with the total HIV DNA reservoir. INTERPRETATION: Expansion and altered features of HIV-specific cTfh cells are maintained during ART and may be driven by persistent HIV antigen expression. FUNDING: This work was supported by the National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR) and the FRQS AIDS and Infectious Diseases Network.

Sleep spindles in chronic psychophysiological insomnia.

OBJECTIVE: A sleep spindle is an electroencephalographic feature that is unique to sleep. It has been suggested that this phasic event has a sleep-protective function. The objective of the present study was to document one aspect of sleep protection in chronic insomnia sufferers: the number and density of sleep spindles in Stage 2 sleep. METHODS: Sleep spindles were scored during Stage 2 sleep on the second and third nights of a protocol of polysomnographic recordings that lasted for four consecutive nights. The sample included 16 participants suffering from insomnia (INS group; mean age=43.4 years) and 14 good sleepers (GS group; mean age=38.1 years). Participants underwent sleep and psychological evaluations. The INS group participants met the diagnostic criteria for primary psychophysiological insomnia (mean duration of insomnia=9.6 years). RESULTS: The total number of sleep spindles in Stage 2 sleep and the density (sleep spindles per minute) according to the total time spent in Stage 2 sleep were compiled. Repeated-measures analyses of variance showed no significant difference in the number and in the density of sleep spindles between the INS group (68.46 and 0.60, respectively) and the GS group (56.28 and 0.46, respectively). CONCLUSION: These results suggest no deficiency in the sleep-protection mechanism of psychophysiological insomnia sufferers in comparison with good sleeper controls, as measured by the number and density of sleep spindles.

Upregulation of IL-32 Isoforms in Virologically Suppressed HIV-Infected Individuals: Potential Role in Persistent Inflammation and Transcription From Stable HIV-1 Reservoirs.

BACKGROUND: Human IL-32 is a polyfunctional cytokine that was initially reported to inhibit HIV-1 infection. However, recent data suggest that IL-32 may enhance HIV-1 replication by activating the HIV-1 primary targets, CD4 T-cells. Indeed, IL-32 is expressed in multiple isoforms, some of which are proinflammatory, whereas others are anti-inflammatory. SETTING AND METHODS: Here, we aimed to determine the relative expression of IL-32 isoforms and to test their inflammatory nature and potential to induce HIV-1 production in latently infected cells from virologically suppressed HIV-infected individuals. IL-32 and other cytokines were quantified from plasma and supernatant of CD4 T-cells by ELISA. Transcripts of IL-32 isoforms were quantified by qRT-PCR in peripheral blood mononuclear cells. The impact of recombinant human IL-32 isoforms on HIV-1 transcription was assessed in CD4 T-cells from HIV-1cART individuals by qRT-PCR. RESULTS: All IL-32 isoforms were significantly upregulated in HIV-1cART compared to HIV individuals with IL-32ß representing the dominantly expressed isoform, mainly in T-cells and NK-cells. At the functional level, although IL-32γ induced typical proinflammatory cytokines (IL-6 and IFN-γ) in TCR-activated CD4 T-cells, IL-32α showed an anti-inflammatory profile by inducing IL-10 but not IL-6 or IFN-γ. However, IL-32ß showed a dual phenotype by inducing both pro- and anti-inflammatory cytokines. Interestingly, consistent with its highly pro-inflammatory nature, IL-32γ, but not IL-32α or IL-32ß, induced HIV-1 production in latently infected CD4 T-cells isolated from combined antiretroviral therapy-treated individuals. CONCLUSIONS: Our data report on the differential expression of IL-32 isoforms and highlight the potential role of IL-32, particularly the γ isoform, in fueling persistent inflammation and transcription of viral reservoir in HIV-1 infection.

Chronic psychophysiological insomnia: hyperarousal and/or inhibition deficits? An ERPs investigation.

STUDY OBJECTIVES: Chronic primary insomnia has been hypothesized to result from conditioned arousal or the inability to initiate normal sleep processes. The event-related potentials (ERPs) N1, P2, and N350 are useful indexes of arousal. The objective is to compare these ERPs in primary chronic psychophysiological insomniacs (INS) and good sleepers (GS) during multiple recordings. PARTICIPANTS: Participants were 15 INS (mean age = 46 years, SD = 7.5) and 16 GS (mean age = 37 years, SD = 10.1). METHODS AND PROCEDURE: Following a multistep clinical evaluation, INS and GS participants underwent 4 consecutive nights of PSG recordings (N1 to N4). ERPs were recorded on the 3rd and 4th nights in the sleep laboratory (N3 and N4). ERPs recordings were made during wake on both nights (in the evening and upon awakening), with the addition of sleep-onset recordings on N4. Auditory stimuli consisted of "standard" and "deviant" tones. STATISTICAL ANALYSIS: Repeated measures ANOVAs were computed for each ERP for each recording for each type of stimulus. RESULTS: The amplitude of P2 and N350 was greater for the deviant than for the standard stimulus in both groups. The amplitude of N1 was larger in INS than GS in the morning and the evening. While the amplitude of N350 was larger in GS than in INS at sleep onset, the amplitude of P2 was greater in INS than in GS at that time. CONCLUSION: Signs of greater cortical arousal in psychophysiological insomnia individuals are observed, especially upon awakening in the morning. However, at sleep onset, difficulties from disengaging from wake processes and some inability at initiating normal sleep processes appear also present in individuals with insomnia compared to good sleepers.

REM sleep as a potential indicator of hyperarousal in psychophysiological and paradoxical insomnia sufferers.

STUDY OBJECTIVES: The objective was to study REM sleep macrostructure and microstructure as potential indicators of hyperarousal in insomnia by comparing good sleepers (GS) and insomnia sufferers (INS) (subdivided into psychophysiological "PSY-I" and paradoxical "PARA-I"). DESIGN: Cross-sectional comparisons of GS, PSY-I and PARA-I. SETTING: Participants slept for 4 consecutive nights in the laboratory where PSG was recorded. Nights 2 and 3 were combined to compare REM sleep between groups. PARTICIPANTS: Thirty-nine PSY-I, 27 PARA-I and 47 GS completed the study, comprising home questionnaires, clinical interviews and night PSG recordings. All participants were aged between 25 and 55 and met inclusion criteria for either PSY-I, PARA-I or GS. INTERVENTIONS N/A MEASUREMENTS AND RESULTS: Results showed no between group differences on REM sleep macrostructure. As for REM sleep microstructure, PSY-I had an increased number of wake intrusions compared to PARA-I (p=.03). Subjective SE, TST and TWT were significantly correlated with the duration of REM sleep (REMD; p≤.002) and with the proportion of REM sleep for PARA-I (p≤.06). CONCLUSIONS: REM sleep macrostructure does not seem to be an adequate indicator of hyperarousal in insomnia. However, the number of wake intrusions in REM could be used to differentiate PSY-I from PARA-I and could reflect the heightened arousal of the former group. Relationships between REM sleep duration and proportion could be linked to dream imagery activity, especially in PARA-I. Further investigations are needed to identify variables that could reflect hyperarousal and differentiate insomnia types.

REM and NREM power spectral analysis on two consecutive nights in psychophysiological and paradoxical insomnia sufferers.

The objectives of the study were to examine EEG activities using power spectral analysis (PSA) of good sleepers (GS), psychophysiological (PsyI) and paradoxical (ParI) insomnia sufferers on two consecutive nights. Participants completed three nights of PSG recordings in a sleep laboratory following a clinical evaluation. Participants were 26 PsyI, 20 ParI and 21 GS (mean age=40 years, SD=9.4). All sleep cycles of Nights 2 and 3 were retained for PSA. The absolute and relative activity in frequency bands (0.00 to 125.00 Hz) were computed at multiple frontal, central and parietal sites in REM and NREM sleep. Mixed model ANOVAs were performed with absolute and relative PSA data to assess differences between groups and nights. Over the course of the two nights, more absolute delta activity at F3, C3, and P3 was observed in ParI compared with PsyI suggesting deactivation of the left hemisphere in ParI and/or hyperactivation in PsyI. Further analysis on absolute PSA data revealed that differences between groups relate mostly to NREM. In REM, lower relative activity in slower frequency bands was found in ParI in comparison with GS and less relative theta activity was found in PsyI compared with GS implying higher activation in insomnia. In addition, between nights variability has been found in absolute powers of faster frequency bands (beta to omega). Signs of decreased cortical activity in absolute PSA in NREM combined with increased relative cortical activation in REM were found in ParI which might contribute to the misperception of sleep in ParI.

Types of primary insomnia: is hyperarousal also present during napping?

STUDY OBJECTIVES: The objective of this study was to identify if hyperarousal is a 24-hour phenomenon in insomnia by comparing sleep during napping between good sleepers (GS) and Insomnia sufferers (INS) (subdivided into paradoxical "PARA-I" and psychophysiological "PSY-I") following a mentally challenging battery of cognitive tests. DESIGN: Cross-sectional comparisons of GS, PSY-I, and PARA-I. SETTING: Participants slept for 4 consecutive nights in the laboratory where PSG was recorded. Upon awakening on mornings 2 and 3, cognitive testing (lasting 90-120 min) was administered, followed by a 20-minute nap. PARTICIPANTS: Fourteen PSY-I, 12 PARA-I, and 23 GS completed the study, comprising home questionnaires, clinical interviews, night PSG recordings, cognitive testing, and nap PSG recordings. All participants were between 25 and 50 years of age and met inclusion criteria for PSY-I, PARA-I, or GS. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: On objective nap parameters, GS had a longer total sleep time (TST; p = 0.008) and better sleep efficiency (SE; p = 0.009), than PSY-I and PARA-I, and both groups of INS were awake significantly longer than GS (p = 0.003). Also, PARA-I took significantly more time than GS to fall asleep (p = 0.014). Subjectively reported sleepiness was comparable across the three groups. Positive relationships were observed between SE over the night and SE over the nap the following day. CONCLUSIONS: Results show that GS sleep better than INS during naps following prolonged cognitive testing, suggesting that, in INS, hyperarousal predominates over mental fatigue resulting from these tests. These results may parallel what is observed at night when INS experience increased cognitive load but are unable to fall asleep.

Cerebral asymmetry in insomnia sufferers.

Cerebral asymmetry is used to describe the differences in electroencephalographic activity between regions of the brain. The objective of this study was to document frontal, central, and parietal asymmetry in psychophysiological (Psy-I) and paradoxical (Para-I) insomnia sufferers as well as good sleeper (GS) controls, and to compare their patterns of asymmetry to others already found in anxiety and depression. Additionally, asymmetry variations between nights were assessed. Participants were 17 Psy-I, 14 Para-I, and 19 GS (mean age = 40 years, SD = 9.4). They completed three nights of polysomnography (PSG) recordings following a clinical evaluation in a sleep laboratory. All sleep cycles of Nights 2 and 3 were retained for power spectral analysis. The absolute activity in frequency bands (0.00-125.00 Hz) was computed at multiple frontal, central, and parietal sites in rapid eye movement and non-rapid eye movement sleep to provide cerebral asymmetry measures. Mixed model ANOVAs were computed to assess differences between groups and nights. Correlations were performed with asymmetry and symptoms of depression and anxiety from self-reported questionnaires. Over the course of the two nights, Para-I tended to present hypoactivation of their left frontal region but hyperactivation of their right one compared with GS. As for Psy-I, they presented increased activation of their right parietal region compared with Para-I. Asymmetry at frontal, central, and parietal region differed between nights. On a more disrupted night of sleep, Psy-I had increased activity in their right parietal region while Para-I presented a decrease in cerebral activity in the right central region on their less disrupted night of sleep. Anxious and depressive symptoms did not correlate with asymmetry at any region. Therefore, Psy-I and Para-I present unique patterns of cerebral asymmetry that do not relate to depression or anxiety, and asymmetry varies between nights, maybe as a consequence of variability in objective sleep quality from night to night.

Are individuals with paradoxical insomnia more hyperaroused than individuals with psychophysiological insomnia? Event-related potentials measures at the peri-onset of sleep.

Preliminary QEEG studies suggest that individuals with paradoxical insomnia (Para-I) display higher cortical arousal than those with psychophysiological insomnia (Psy-I). Lately, finer measures, such as event-related potentials, and especially the N1 and P2 components have been used to document arousal processes in individuals with insomnia. The objective of the present study was to further circumscribe arousal in Psy-I and Para-I using N1, P2 and the waking processing negativity (wPN). N1 and P2 were recorded in the evening, at sleep-onset and in early stage 2 sleep in 26 good sleepers, 26 Psy-I and 26 Para-I. An oddball paradigm was used and participants received the instruction to ignore all stimuli at all times. Three difference waves (wPNs) were computed to evaluate the transition from wakefulness to sleep onset, from sleep onset to sleep and from wakefulness to sleep. Results revealed that N1 was smaller during wakefulness and sleep onset for Psy-I, while it was larger for Para-I during these same times. P2 was smaller at sleep onset for Psy-I than for Para-I and GS, while P2 during wakefulness and stage 2 sleep was larger for Para-I than GS. WPNs revealed that Psy-I showed fewer changes in information processing, while Para-I showed larger changes between recording times. Psy-I appear to present an inability to inhibit information processing during sleep onset, while Para-I seem to present overall enhanced attentional processing that results in a greater need for inhibition.

Is quality of sleep related to the N1 and P2 ERPs in chronic psychophysiological insomnia sufferers?

INTRODUCTION: Our recent ERPs study suggested inhibition deficits in addition to cortical arousal in insomnia sufferers (INS) relative to good sleepers (GS). The aim of the present study was to investigate the relation between objective sleep parameters and the amplitudes and latencies of ERPs components N1 and P2 in a multi-assessment protocol. METHODS: Participants, 15 INS and 16 GS, underwent four consecutive nights of polysomnography recordings (N1 to N4). ERPs in the evening and upon awakening were recorded on N3 and N4, with the addition of sleep-onset recordings on N4. Auditory stimuli consisted of 'standard' and 'deviant' tones. Objective sleep measures were computed on each night [sleep efficiency (SE), wake after sleep onset (WASO), total sleep time (TST) and sleep-onset latency (SOL)]. The amplitude and latency of N1 and P2 components were assessed for each recorded session on each night and related to measures of sleep of the same nights (N3 and N4). RESULTS: Pearson's correlations between the amplitude and latency of N1 and P2 and objective sleep measures revealed that arousal levels in the evening, before going to bed seem to have an impact on subsequent sleep quality. Furthermore, the sleep quality of the previous night also appeared to have an impact on morning (daily) arousal levels. CONCLUSION: These results suggest that hyperactivation and inhibition deficits present in insomnia sufferers are directly associated with a poorer sleep quality. This highlights once again that when information processing and/or performance is assessed, the sleep quality of the night preceding the evaluation shall be documented.

Spontaneous K-complexes in chronic psychophysiological insomnia.

OBJECTIVE: Spontaneous K-complexes are electroencephalographic features unique to non-rapid eye movement sleep. It has been suggested that this phasic event is a sleep-protective mechanism. Because insomnia sufferers report poor sleep quantity and quality, the objective of this study was to document the occurrence of spontaneous K-complexes in Stage 2 sleep of individuals with chronic insomnia. Specifically, the number and density of spontaneous K-complexes were studied in psychophysiological insomnia sufferers. SETTING: This study took place in a sleep and event-related potentials laboratory. DESIGN: Spontaneous K-complexes were scored during Stage 2 sleep on the second and third nights of a four-consecutive-nights protocol of polysomnographic recordings. PARTICIPANTS: The sample included 14 participants suffering from psychophysiological insomnia (INS group; mean age=44.1 years) and 14 good sleepers (mean age=38.1 years). Participants underwent sleep and psychological evaluations. INS group participants met the diagnostic criteria for primary psychophysiological insomnia (mean duration of insomnia=9.6 years). INTERVENTION: Not applicable. RESULTS: The total number of spontaneous K-complexes and the density according to the total time spent in Stage 2 sleep (spontaneous K-complexes per minute) were compiled. Repeated-measures analyses of variance showed no significant difference in the number and density of spontaneous K-complexes between the INS group (313.98 and 2.66) and the GS group (361.10 and 2.88), respectively. CONCLUSION: These results suggest no deficiency in the sleep-protective mechanism of psychophysiological insomnia sufferers in comparison with good sleepers, as measured by the spontaneous K-complexes' number and density.