A Bayesian approach for investigating the pharmacogenetics of combination antiretroviral therapy in people with HIV.

Combination antiretroviral therapy (ART) with at least three different drugs has become the standard of care for people with HIV (PWH) due to its exceptional effectiveness in viral suppression. However, many ART drugs have been reported to associate with neuropsychiatric adverse effects including depression, especially when certain genetic polymorphisms exist. Pharmacogenetics is an important consideration for administering combination ART as it may influence drug efficacy and increase risk for neuropsychiatric conditions. Large-scale longitudinal HIV databases provide researchers opportunities to investigate the pharmacogenetics of combination ART in a data-driven manner. However, with more than 30 FDA-approved ART drugs, the interplay between the large number of possible ART drug combinations and genetic polymorphisms imposes statistical modeling challenges. We develop a Bayesian approach to examine the longitudinal effects of combination ART and their interactions with genetic polymorphisms on depressive symptoms in PWH. The proposed method utilizes a Gaussian process with a composite kernel function to capture the longitudinal combination ART effects by directly incorporating individuals' treatment histories, and a Bayesian classification and regression tree to account for individual heterogeneity. Through both simulation studies and an application to a dataset from the Women's Interagency HIV Study, we demonstrate the clinical utility of the proposed approach in investigating the pharmacogenetics of combination ART and assisting physicians to make effective individualized treatment decisions that can improve health outcomes for PWH.

Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

A Systematic Review and Meta-Analysis of Social Cognition Among People Living with HIV: Implications for Non-Social Cognition and Social Everyday Functioning.

Social cognition-the complex mental ability to perceive social stimuli and negotiate the social environment-has emerged as an important cognitive ability needed for social functioning, everyday functioning, and quality of life. Deficits in social cognition have been well documented in those with severe mental illness including schizophrenia and depression, those along the autism spectrum, and those with other brain disorders where such deficits profoundly impact everyday life. Moreover, subtle deficits in social cognition have been observed in other clinical populations, especially those that may have compromised non-social cognition (i.e., fluid intelligence such as memory). Among people living with HIV (PLHIV), 44% experience cognitive impairment; likewise, social cognitive deficits in theory of mind, prosody, empathy, and emotional face recognition/perception are gradually being recognized. This systematic review and meta-analysis aim to summarize the current knowledge of social cognitive ability among PLHIV, identified by 14 studies focused on social cognition among PLHIV, and provides an objective consensus of the findings. In general, the literature suggests that PLHIV may be at-risk of developing subtle social cognitive deficits that may impact their everyday social functioning and quality of life. The causes of such social cognitive deficits remain unclear, but perhaps develop due to (1) HIV-related sequelae that are damaging the same neurological systems in which social cognition and non-social cognition are processed; (2) stress related to coping with HIV disease itself that overwhelms one's social cognitive resources; or (3) may have been present pre-morbidly, possibly contributing to an HIV infection. From this, a theoretical framework is proposed highlighting the relationships between social cognition, non-social cognition, and social everyday functioning.

A positive affect intervention alters leukocyte DNA methylation in sexual minority men with HIV who use methamphetamine.

OBJECTIVE: This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm). METHODS: Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control - an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes. RESULTS: Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate ß2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use. CONCLUSIONS: There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses.

Social support network factors associated with verbal fluency among vulnerable persons living with HIV.

Vulnerable persons living with HIV (PLWH) are at high risk of cognitive impairment and challenges accessing quality social support in later life. Impaired verbal fluency (VF), a cognitive domain linked to HIV, could impede social support associated with health and well-being for already vulnerable PLWH. We examined the structure of social support, using latent class analysis, and the associations among quantity, specific forms and quality of social support and VF among PLWH. Participants enrolled in the BEACON study (n = 383) completed the Controlled Oral Word Association test (COWAT) and a social support network inventory. Latent class analysis with count variables was used to determine the number of classes of PLWH based on their social network characteristics. The majority of PLWH were male (61.4%) and African American (85.9%). Two distinct latent classes, with a major distinction in the number of network members who were female, knew participants' HIV status and HIV medication usage. Fewer support network members (ß = -.13, p < 0.01), greater negative interactions (ß = -.16, p < 0.01), and less positive interactions with network members (ß = .15, p < 0.05) were significantly associated with lower COWAT scores. Comprehensive screening of high-risk PLWH and early intervention with those with cognitive impairment are important for addressing social support needs.

Twelve-year neurocognitive decline in HIV is associated with comorbidities, not age: a CHARTER study.

Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (<60 years) and older (≥60 years) subgroups. Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.

The Evolution of Assessing Central Nervous System Complications in Human Immunodeficiency Virus: Where Do We Go From Here?

In this fifth decade of the human immunodeficiency virus (HIV) epidemic, central nervous system (CNS) complications including cognitive impairment and mental health remain a burden for people with HIV (PWH) on antiretroviral therapy. Despite the persistence of these complications, which often co-occur, the underlying pathophysiology remains elusive and consequently treatments remain limited. To continue to grow our understanding of the underlying mechanisms of CNS complications among PWH, there is a need to reexamine our current approaches, which are now more than 2 decades old. At the 2021 National Institutes of Health-sponsored meeting on Biotypes of CNS Complications in PWH, the Neurobehavioral Working Group addressed the following: (1) challenges inherent to determining CNS complications; (2) heterogeneity in CNS complications; and (3) problems and solutions for examining integrated biotypes. The review below provides a summary of the main points presented and discussed by the Neurobehavioral Working Group at the meeting.

Higher Levels of Cerebrospinal Fluid and Plasma Neurofilament Light in Human Immunodeficiency Virus-Associated Distal Sensory Polyneuropathy.

BACKGROUND: Neurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH). METHODS: Cohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2. RESULTS: Cohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds. CONCLUSIONS: Both plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Trauma Across the Life Span and Multisystem Morbidity in Women With HIV.

OBJECTIVE: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes. METHODS: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes. RESULTS: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8. CONCLUSIONS: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.

Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis.

INTRODUCTION: High-inflammation subgroups of patients with psychosis demonstrate cognitive deficits and neuroanatomical alterations. Systemic inflammation assessed using IL-6 and C-reactive protein may alter functional connectivity within and between resting-state networks, but the cognitive and clinical implications of these alterations remain unknown. We aim to determine the relationships of elevated peripheral inflammation subgroups with resting-state functional networks and cognition in psychosis spectrum disorders. METHODS: Serum and resting-state fMRI were collected from psychosis probands (schizophrenia, schizoaffective, psychotic bipolar disorder) and healthy controls (HC) from the B-SNIP1 (Chicago site) study who were stratified into inflammatory subgroups based on factor and cluster analyses of 13 cytokines (HC Low n = 32, Proband Low n = 65, Proband High n = 29). Nine resting-state networks derived from independent component analysis were used to assess functional and multilayer connectivity. Inter-network connectivity was measured using Fisher z-transformation of correlation coefficients. Network organization was assessed by investigating networks of positive and negative connections separately, as well as investigating multilayer networks using both positive and negative connections. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia. Linear regressions, Spearman correlations, permutations tests and multiple comparison corrections were used for analyses in R. RESULTS: Anterior default mode network (DMNa) connectivity was significantly reduced in the Proband High compared to Proband Low (Cohen's d = -0.74, p = 0.002) and HC Low (d = -0.85, p = 0.0008) groups. Inter-network connectivity between the DMNa and the right-frontoparietal networks was lower in Proband High compared to Proband Low (d = -0.66, p = 0.004) group. Compared to Proband Low, the Proband High group had lower negative (d = 0.54, p = 0.021) and positive network (d = 0.49, p = 0.042) clustering coefficient, and lower multiplex network participation coefficient (d = -0.57, p = 0.014). Network findings in high inflammation subgroups correlate with worse verbal fluency, verbal memory, symbol coding, and overall cognition. CONCLUSION: These results expand on our understanding of the potential effects of peripheral inflammatory signatures and/or subgroups on network dysfunction in psychosis and how they relate to worse cognitive performance. Additionally, the novel multiplex approach taken in this study demonstrated how inflammation may disrupt the brain's ability to maintain healthy co-activation patterns between the resting-state networks while inhibiting certain connections between them.

Selection of cognitive impairment screening tools for longitudinal implementation in an HIV clinical care setting.

To address and slow the increasing burden of cognitive impairment in people surviving to older ages with HIV requires longitudinal monitoring of cognition. We conducted a structured literature review to identify peer-reviewed studies employing validated cognitive impairment screening tools in adult populations of people with HIV. We identified three key criteria for selection and ranking of a tool: (a) strength of validity of the tool; (b) acceptability and feasibility of the tool; (c) ownership of the data from the assessment. From our structured review of 105, 29 studies met our inclusion criteria, within which 10 cognitive impairment screening measurement tools were validated in a population of people with HIV. The BRACE, NeuroScreen and NCAD tools were ranked highly when compared with the other seven tools. Additionally, patient population and clinical setting characteristics (such as availability of quiet space, timing of assessment, security of electronic resources, and ease of linkage to electronic health records) were included in our framework for selection of tools. Numerous validated cognitive impairment screening tools are available to monitor for cognitive changes in the HIV clinical care setting, detecting opportunities for earlier intervention to reduce cognitive decline and preserve quality of life.

Higher buccal mitochondrial DNA and mitochondrial common deletion number are associated with markers of neurodegeneration and inflammation in cerebrospinal fluid.

Human immunodeficiency virus (HIV) infection is potentially associated with premature aging, but demonstrating this is difficult due to a lack of reliable biomarkers. The mitochondrial (mt) DNA "common deletion" mutation (mtCDM) is a 4977-bp deletion associated with aging and neurodegenerative diseases. We examined how mtDNA and mtCDM correlate with markers of neurodegeneration and inflammation in people with and without HIV (PWH and PWOH). Data from 149 adults were combined from two projects involving PWH (n = 124) and PWOH (n = 25). We measured buccal mtDNA and mtCDM by digital droplet PCR and compared them to disease and demographic characteristics and soluble biomarkers in cerebrospinal fluid (CSF) and blood measured by immunoassay. Participants had a median age of 52 years, with 53% white and 81% men. Median mtDNA level was 1,332 copies/cell (IQR 1,201-1,493) and median mtCDM level was 0.36 copies × 102/cell (IQR 0.31-0.42); both were higher in PWH. In the best model adjusting for HIV status and demographics, higher mtDNA levels were associated with higher CSF amyloid-ß 1-42 and 8-hydroxy-2'-deoxyguanosine and higher mtCDM levels were associated with higher plasma soluble tumor necrosis factor receptor II. The differences in mtDNA markers between PWH and PWOH support potential premature aging in PWH. Our findings suggest mtDNA changes in oral tissues may reflect CNS processes, allowing the use of inexpensive and easily accessible buccal biospecimens as a screening tool for CSF inflammation and neurodegeneration. Confirmatory and mechanistic studies on mt genome alterations by HIV and ART may identify interventions to prevent or treat neurodegenerative complications.

The Interaction of HIV With Mental Health in the Modern Antiretroviral Therapy Era.

ABSTRACT: People with HIV (PWH) receiving effective antiretroviral therapy (ART) continue to display residual immune dysregulation that amplifies the risk for neuropsychiatric comorbidities. At the same time, PWH commonly experience intersectional stigma and other psychosocial stressors that are linked to neuroendocrine stress responses, potentiate residual immune dysregulation, and alter other biobehavioral processes relevant to health outcomes. This special issue of Psychosomatic Medicine seeks to advance our understanding of the intersection of HIV with mental health in the modern ART era. Several articles cover topics related to the prevalence and treatment of psychiatric comorbidities among PWH such as depression, suicidality, and substance use disorders. Other articles delineate biobehavioral mechanisms relevant to mental health in PWH such as inflammation, immune activation, neuroendocrine signaling, cellular aging, the microbiome-gut-brain axis, and neurobehavioral processes. Collectively, the articles in this special issue highlight the continued importance of biobehavioral and neurobehavioral mental health research in the modern ART era.

The Association Between Peripheral Oxytocin Levels and Depressive Symptoms in People With HIV.

OBJECTIVE: Depression is common in people with HIV (PWH), yet little is known about the mechanisms contributing to depressive symptoms in PWH. Previous research across a range of populations has suggested a relationship between the neuropeptide oxytocin and depressive symptoms, with variable directionality. This article investigated the association between peripheral oxytocin levels and depressive symptoms in PWH. METHODS: Unextracted oxytocin serum concentrations were assayed in 79 PWH (44% female, mean age = 34.35 [8.5], mean body mass index = 25.69 [5.46], mean CD4 = 516.60 [271.15]) who also completed the Center for Epidemiologic Studies Depression Scale (CES-D). CES-D items were evaluated in an exploratory factor analysis (EFA), and the relationships between oxytocin, total CES-D score, and the resulting EFA factors were analyzed with multivariate linear regressions conducted in R. Multiple regression models were used to adjust for age, sex, body mass index, CD4, and education. RESULTS: Contrary to hypothesized, higher peripheral oxytocin levels were associated with higher CES-D total scores with a small-to-moderate effect size ( ß = 0.26, p = .009). Following Bonferroni correction, oxytocin was not significantly associated with any of the five factors identified from the EFA: depressed affect, positive affect, appetite, cognitive symptoms, or perceived failure ( p values > .042). Small effect sizes were found for the depressed affect ( ß = 0.22) and perceived failure ( ß = 0.21) factors ( p values > .042). CONCLUSIONS: In a sample of predominately Black or African American individuals with HIV, higher oxytocin was associated with higher total depressive symptoms. In addition, this relationship was slightly stronger than those of specific depressive symptoms. These findings warrant further study into the role of oxytocin in mood symptoms within PWH.

Through the Looking-Glass: Psychoneuroimmunology and the Microbiome-Gut-Brain Axis in the Modern Antiretroviral Therapy Era.

OBJECTIVE: Depression, substance use disorders, and other neuropsychiatric comorbidities are common in people with HIV (PWH), but the underlying mechanisms are not sufficiently understood. HIV-induced damage to the gastrointestinal tract potentiates residual immune dysregulation in PWH receiving effective antiretroviral therapy. However, few studies among PWH have examined the relevance of microbiome-gut-brain axis: bidirectional crosstalk between the gastrointestinal tract, immune system, and central nervous system. METHODS: A narrative review was conducted to integrate findings from 159 articles relevant to psychoneuroimmunology (PNI) and microbiome-gut-brain axis research in PWH. RESULTS: Early PNI studies demonstrated that neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis and autonomic nervous system could partially account for the associations of psychological factors with clinical HIV progression. This review highlights the need for PNI studies examining the mechanistic relevance of the gut microbiota for residual immune dysregulation, tryptophan catabolism, and oxytocin release as key biological determinants of neuropsychiatric comorbidities in PWH (i.e., body-to-mind pathways). It also underscores the continued relevance of neuroendocrine signaling via the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and oxytocin release in modifying microbiome-gut-brain axis functioning (i.e., mind-to-body pathways). CONCLUSIONS: Advancing our understanding of PNI and microbiome-gut-brain axis pathways relevant to depression, substance use disorders, and other neuropsychiatric comorbidities in PWH can guide the development of novel biobehavioral interventions to optimize health outcomes. Recommendations are provided for biobehavioral and neurobehavioral research investigating bidirectional PNI and microbiome-gut-brain axis pathways among PWH in the modern antiretroviral therapy era.

Early Life Trauma and Social Processing in HIV: The Role of Neuroendocrine Factors and Inflammation.

OBJECTIVE: Early life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association. METHODS: We used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations. RESULTS: Of 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized ß [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05). CONCLUSIONS: Our pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus-Infected Pigtail Macaques ( Macaca nemestrina ) as a Model of Psychosocial Stress in Acute HIV Infection.

OBJECTIVE: Simian immunodeficiency virus (SIV) infection of macaques recapitulates many aspects of HIV pathogenesis and is similarly affected by both genetic and environmental factors. Psychosocial stress is associated with immune system dysregulation and worse clinical outcomes in people with HIV. This study assessed the impact of single housing, as a model of psychosocial stress, on innate immune responses of pigtailed macaques ( Macaca nemestrina ) during acute SIV infection. METHODS: A retrospective analysis of acute SIV infection of 2- to si6-year-old male pigtailed macaques was performed to compare the innate immune responses of socially ( n = 41) and singly ( n = 35) housed animals. Measures included absolute monocyte count and subsets, and in a subset ( n ≤ 18) platelet counts and activation data. RESULTS: SIV infection resulted in the expected innate immune parameter changes with a modulating effect from housing condition. Monocyte number increased after infection for both groups, driven by classical monocytes (CD14 + CD16 - ), with a greater increase in socially housed animals (227%, p < .001, by day 14 compared with preinoculation time points). Platelet numbers recovered more quickly in the socially housed animals. Platelet activation (P-selectin) increased by 65% ( p = .004) and major histocompatibility complex class I surface expression by 40% ( p = .009) from preinoculation only in socially housed animals, whereas no change in these measures occurred in singly housed animals. CONCLUSIONS: Chronic psychosocial stress produced by single housing may play an immunomodulatory role in the innate immune response to acute retroviral infection. Dysregulated innate immunity could be one of the pathways by which psychosocial stress contributes to immune suppression and increased disease severity in people with HIV.

Cognitive Intra-individual Variability in HIV: an Integrative Review.

Nearly 30-50% of people living with HIV experience HIV-Associated Neurocognitive Disorder (HAND). HAND indicates performance at least one standard deviation below the normative mean on any two cognitive domains. This method for diagnosing or classifying cognitive impairment has utility, however, cognitive intraindividual variability provides a different way to understand cognitive impairment. Cognitive intraindividual variability refers to the scatter in cognitive performance within repeated measures of the same cognitive test (i.e., inconsistency) or across different cognitive tests (i.e., dispersion). Cognitive intraindividual variability is associated with cognitive impairment and cognitive decline in various clinical populations. This integrative review of 13 articles examined two types of cognitive intraindividual variability in people living with HIV, inconsistency and dispersion. Cognitive intraindividual variability appears to be a promising approach to detect subtle cognitive impairments that are not captured by traditional mean-based neuropsychological testing. Greater intraindividual variability in people living with HIV has been associated with: 1) poorer cognitive performance and cognitive decline, 2) cortical atrophy, both gray and white matter volume, 3) poorer everyday functioning (i.e., driving simulation performance), specifically medication adherence, and 4) even mortality. This inspires future directions for research. First, greater cognitive intraindividual variability may reflect a greater task demand on executive control to harness and regulate cognitive control over time. By improving executive functioning through cognitive training, it may reduce cognitive intraindividual variability which could slow down cognitive decline. Second, cognitive intraindividual variability may be reconsidered in prior cognitive intervention studies in which only mean-based cognitive outcomes were used. It is possible that such cognitive interventions may actually improve cognitive intraindividual variability, which could have clinical relevance.