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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 ( 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.

Determination of functional capacity in cognitively impaired persons living with HIV (PLHIV) is pivotal to the accurate diagnosis of HIV-associated neurocognitive disorders (HAND). Functional data is typically collected through self-report. Reliability concerns arise with memory and executive functioning impairments, which could compromise the integrity of self-report and result in inaccurate HAND diagnoses. The current study tested the accuracy of older PLHIV functional reports through examination of concordance rates between self-report and caregiver's (CG) report. Cross-sectional cognitive, mood, and functional status data were sampled from the Manhattan HIV Brain Bank. Participants and caregivers independently completed an Activities of Daily Living (ADL) questionnaire, producing 78 participant-caregiver dyads. Functional report concordance was operationalized by calculating differences between participant and CG ADL total scores. Assessment pairs differing by 2 or more points were considered to be discordant. Analyses revealed that one-third of the patient sample was discordant in the ADL report. ANOVA revealed that PLHIV overestimating their functional impairments, were significantly older, more educated, and more depressed than other participants. Global cognitive functioning was not associated with concordance. Thus, the majority of PLHIV were consistent with their caregivers' ADL report, and older age and increased depressive symptomatology, but not cognitive status, were factors associated with discordance.

Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

Background Hypertension and HIV are salient risk factors for cerebral small vessel disease and neurocognitive impairment, yet the effects of hypertension on neurocognitive performance in persons living with HIV remain poorly understood. This is the first study to examine the longitudinal associations between blood pressure, hypertension, and pulse pressure with neurocognitive performance in persons living with HIV. Setting New York City. Methods Analysis of medical, neurocognitive, and virologic data from 485 HIV+ participants collected by the Manhattan HIV Brain Bank, a prospective, observational, longitudinal study of neuroHIV. A series of multilevel linear growth curve models with random intercepts and slopes were estimated for blood pressure, hypertension status, and pulse pressure to predict change in neurocognitive performance. Results The baseline prevalence of hypertension was 23%. Longitudinal change in diastolic and systolic pressure were associated with 10.5-second and 4-second increase in Grooved Pegboard Test non-dominant hand performance, respectively. Longitudinal change in diastolic blood pressure was also associated a .3-point decline in correct categories and 3-point increase in perseverative responses and total errors on the Wisconsin Card Sorting Test. Increasing odds of prevalent and/or incident hypertension was associated with a .1-point decrease in correct categories and a .8-point increase in total errors on the Wisconsin Card Sorting Test. There was no association between pulse pressure and neurocognitive performance. Conclusions Results indicate linear longitudinal relations for blood pressure and hypertension with poorer neurocognitive test performance, particularly in psychomotor and executive functions in persons with HIV.

Objectives Few publications have documented the utility of in-home telephone-based cognitive screeners during COVID-19. This manuscript describes the adaptation of select face-to-face (FTF) neuropsychological tests to telephonic administration in a longitudinal cohort of people with HIV (PWH). Using the cohort’s pre-pandemic neuropsychological data, we explore the utility of telephonic administration in this population. Methods Of a longitudinal cohort of 170 adult PWH, 59 completed telephonic medical and cognitive screenings with comparable pre-pandemic FTF data. Telephone screeners and FTF evaluations were compared using repeated measures ANCOVAs to examine whether test performance differed between administration types and levels of pre-pandemic cognitive performance. Individuals with pre-pandemic test scores more than a standard deviation below the demographically-corrected mean were categorized as “below average” cognitive performance (n = 23), and the remainder as “average” (n = 36). Results Over 90% of participants gave positive feedback about the telephone encounter. The average cognitive performance group scored higher than the below average group on all measures across both administration types. Telephone and FTF test scores did not differ significantly for measures of category fluency, letter fluency, and verbal learning. However, the below average group scored higher on a verbal memory measure administered via telephone compared with FTF. Conclusions Support for telephonic adaptation of select FTF measures in longitudinal research is mixed, with verbal fluency tasks showing the strongest equivalency. When employed carefully with a clear understanding of their limitations, telephone adaptations can provide an opportunity to continue study objectives, promote equity, and monitor participant well-being during times of duress.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.

Background The prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART. Methods This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry. Results Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3–4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations. Conclusions These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting., Depression is a major challenge for people with human immunodeficiency virus (HIV). Adults with depressive symptoms had lower neuroactive steroid metabolites than those without depressive symptoms, highlighting the importance of hypothalamic-pituitary-adrenal axis dysregulation in HIV-infected adults with depression.

Exploration of genome organization and function in the HIV infected brain is critical to aid in the development of treatments for HIV-associated neurocognitive disorder (HAND) and HIV cure strategies. Here, we generated a resource comprised of single nuclei transcriptomics, complemented by cell-type-specific Hi-C chromosomal conformation (‘3D genome’) and viral integration site sequencing (IS-seq) in frontal brain tissues from individuals with HIV encephalitis (HIVE), HIV-infected people without encephalitis (HIV+), and HIV uninfected (HIV-) controls. We observed profound 3D genomic reorganization of open/repressive (A/B) compartment structures encompassing 6.4% of the HIVE microglial genome that was associated with transcriptomic reprogramming, including down-regulation of homeostasis and synapse-related functions and robust activation of interferon signaling and cell migratory pathways. HIV RNA was detected in 0.003% of all nuclei in HIVE brain, predominantly in the most activated microglia where it ranked as the second most highly expressed transcript. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 insertion events in glial nuclei that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Brain and peripheral myeloid cell integration revealed a preference overall for transcription-permissive chromatin, but robust differences in the frequency of recurrent insertions, intergenic integration, and enrichment for pre-integration complex-associated factors at integration sites. Our resource highlights critical differences in the genomic patterns of HIV infection in brain versus blood and points to a dynamic interrelationship between inflammation-associated 3D genome remodeling and successful integration in brain.

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 52years, 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-β 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.

Microglia are implicated in Alzheimer’s Disease (AD) pathogenesis. In a middle-aged cohort enriched for neuroinflammation, we asked whether microgliosis was related to neocortical amyloid beta (A$$\upbeta$$ β ) deposition and neuronal phosphorylated tau (p-tau), and whether microgliosis predicted cognition. Frontal lobe tissue from 191 individuals autopsied with detectable (HIV-D) and undetectable (HIV-U) HIV infection, and 63 age-matched controls were examined. Immunohistochemistry (IHC) was used to evaluate A$$\upbeta$$ β plaques and neuronal p-tau, and quantitate microgliosis with markers Iba1, CD163, and CD68 in large regions of cortex. Glia in the A$$\upbeta$$ β plaque microenvironment were quantitated by immunofluorescence (IF). The relationship of microgliosis to cognition was evaluated. No relationship between A$$\upbeta$$ β or p-tau accumulation and overall severity of microgliosis was discerned. Individuals with uncontrolled HIV had the greatest microgliosis, but fewer A$$\upbeta$$ β plaques; they also had higher prevalence of APOE $$\upvarepsilon$$ ε 4 alleles, but died earlier than other groups. HIV group status was the only variable predicting microgliosis over large frontal regions. In contrast, in the A$$\upbeta$$ β plaque microenvironment, APOE $$\upvarepsilon$$ ε 4 status and sex were dominant predictors of glial infiltrates, with smaller contributions of HIV status. Cognition correlated with large-scale microgliosis in HIV-D, but not HIV-U, individuals. In this autopsy cohort, over large regions of cortex, HIV status predicts microgliosis, whereas in the A$$\upbeta$$ β plaque microenvironment, traditional risk factors of AD (APOE $$\upvarepsilon$$ ε 4 and sex) are stronger determinants. While microgliosis does not predict neurodegenerative protein deposition, it does predict cognition in HIV-D. Increased neuroinflammation does not initiate amyloid deposition in a younger group with enhanced genetic risk. However, once A$$\upbeta$$ β deposits are established, APOE $$\upvarepsilon$$ ε 4 predicts increased plaque-associated inflammation.

Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

BackgroundEpigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlates with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals.MethodsWe used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen, and pituitary gland) from 133 clinically-characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history.ResultsEpigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung, and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multi-organ impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that Amyotrophic Lateral Sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues.ConclusionBlood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

BACKGROUND AND PURPOSE People with human immunodeficiency virus (HIV; PWH) present a complex array of immunologic and medical disorders that impact brain structure and metabolism, complicating the interpretation of neuroimaging. This pilot study of well-characterized multi-morbid PWH examined how medical and immunologic factors predicted brain characteristics on proton MR spectroscopy (1H-MRS) and diffusion-weighted imaging (DWI). METHODS Eighteen individuals on combination antiretroviral therapy (cART), with mean age of 56 years, underwent medical history review, neuroimaging, and on the day of imaging, blood draw for assay of 20 plasma cytokines and flow cytometric characterization of peripheral blood mononuclear cell subsets. Predictors of n-acetyl aspartate, choline, myoinositol, glutamate/glutamine, fractional anisotropy and mean diffusivity were identified through bivariate correlation; those significant at p < .1000 were advanced to multivariate analysis, with models created for each neuroimaging outcome. RESULTS Monocyte subsets and diverse cytokines accounted for 16 of 25 (64%) variables predicting 1H-MRS spectra in frontal gray and white matter and basal ganglia; monocyte subsets did not predict any DWI characteristic. In contrast, age, presence of hypertension, and duration of HIV infection accounted for 13 of 25 (52%) variables predicting diffusion characteristics in the corpus callosum, thalamic radiations, and basal ganglia but only 3 of 25 (12%) predictors of 1H-MRS features. CONCLUSIONS 1H-MRS neurometabolites were most often predicted by immunologic factors sensitive to temporal variation, whereas DWI metrics were more often related to longer-term disease state. In multi-morbid cART-era populations, selection and interpretation of neuroimaging modalities should account for complex temporal and pathogenetic influences of immunologic abnormality, disease state, and aging.

Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in the brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV- controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, CHOP, CASP1, WARS) gene expression changes are associated with decreased energy metabolism (SREBF1, SREBF2, PARK2, TXNIP) and oligodendrocyte myelin production (MAG, MOG), leading to white matter dysfunction. Machine learning identified a 15-gene signature predictive of HIV status that was validated in an independent cohort. No specific gene expression patterns were associated with NCI. These findings suggest therapies that decrease chronic inflammation while protecting mitochondrial function may help to preserve white matter integrity in older HIV+ individuals.

Objective:Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.Method:Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.Results:When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.Conclusions:The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

Objective: Atherosclerotic cardiovascular disease (ASCVD) is an increasing cause of morbidity and mortality in people with HIV since the introduction of combination antiretroviral therapy. Despite recent advances in our understanding of HIV ASCVD, controversy still exists on whether this increased risk of ASCVD is due to chronic HIV infection or other risk factors. Mounting biomarker studies indicate a role of monocyte/macrophage activation in HIV ASCVD; however, little is known about the mechanisms through which HIV infection mediates monocyte/macrophage activation in such a way as to engender accelerated atherogenesis. Here, we experimentally investigated whether HIV expression is sufficient to accelerate atherosclerosis and evaluated the role of caspase-1 activation in monocytes/macrophages in HIV ASCVD. Approach and Results: We crossed a well-characterized HIV mouse model, Tg26 mice, which transgenically expresses HIV-1, with ApoE −/− mice to promote atherogenic conditions ( Tg26 +/− / ApoE −/− ). Tg26 +/− /ApoE −/− have accelerated atherosclerosis with increased caspase-1 pathway activation in inflammatory monocytes and atherosclerotic vasculature compared with ApoE −/− . Using a well-characterized cohort of people with HIV and tissue-banked aortic plaques, we documented that serum IL (interleukin)-18 was higher in people with HIV compared with non–HIV-infected controls, and in patients with plaques, IL-18 levels correlated with monocyte/macrophage activation markers and noncalcified inflammatory plaques. In autopsy-derived aortic plaques, caspase-1+ cells and CD (clusters of differentiation) 163+ macrophages correlated. Conclusions: These data demonstrate that expression of HIV is sufficient to accelerate atherogenesis. Further, it highlights the importance of caspase-1 and monocyte/macrophage activation in HIV atherogenesis and the potential of Tg26 +/− /ApoE −/− as a tool for mechanistic studies of HIV ASCVD.

Summary Background Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p Interpretation The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

Author(s): Saloner, Rowan; Heaton, Robert K; Campbell, Laura M; Chen, Anna; Franklin, Donald; Ellis, Ronald J; Collier, Ann C; Marra, Christina; Clifford, David B; Gelman, Benjamin; Sacktor, Ned; Morgello, Susan; McCutchan, J Allen; Letendre, Scott; Grant, Igor; Fennema-Notestine, Christine; CHARTER Study Group | Abstract: ObjectiveThe influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.DesignObservational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.MethodsA total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.ResultsComorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).ConclusionNeuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.

Author(s): Saloner, Rowan; Campbell, Laura M; Serrano, Vanessa; Montoya, Jessica L; Pasipanodya, Elizabeth; Paolillo, Emily W; Franklin, Donald; Ellis, Ronald J; Letendre, Scott L; Collier, Ann C; Clifford, David B; Gelman, Benjamin B; Marra, Christina M; McCutchan, J Allen; Morgello, Susan; Sacktor, Ned; Jeste, Dilip V; Grant, Igor; Heaton, Robert K; Moore, David J; CHARTER and HNRP Groups | Abstract: OBJECTIVES:Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. METHODS:734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. RESULTS:Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. CONCLUSIONS:Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507-519).

Objective Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. Methods This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. Results Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). Conclusions Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Author(s): Lorenz, David R; Mukerji, Shibani S; Misra, Vikas; Uno, Hajime; Gelman, Benjamin B; Moore, David J; Singer, Elyse J; Morgello, Susan; Gabuzda, Dana | Abstract: ObjectivePeople with human immunodeficiency virus (HIV) (PWH) have increased prevalence of multimorbidity and frailty at younger ages compared to the general population. This study investigated individual and combinatorial effects of neuropsychiatric and medical comorbidities as predictors of frailty in PWH.DesignAnalysis of data from the National NeuroAIDS Tissue Consortium, a longitudinal observational cohort.Methods524 PWH over age 40 were classified using Fried's Frailty criteria. Twelve comorbidities were documented from longitudinal data and associations between individual and co-occurring comorbidities with frailty were assessed using weighted network and logistic regression analyses.ResultsAt frailty assessment between 2015-2020, median age was 61 years, 76% were male, 94% were on ART, 73% had two or more comorbidities, 24% were frail, and 52% were prefrail. Among individual comorbidities, highest odds of frailty were in participants with depressive symptoms (adjusted odds ratio [aOR], 95% confidence interval [CI] 3.48 [2.22-5.46]]), followed by bone disease and COPD (2.47 [1.28-4.72] and 2.13 [1.36-3.34], respectively). Among co-occurring comorbidities, highest odds of frailty were in participants having depressive symptoms with diabetes, hypertension, or obesity (aORs [95% CIs] 5.29 [2.32-12.08], 5.21 [2.65-10.40], 4.85 [2.39-9.95], respectively), cognitive impairment with diabetes or renal disease, (2.81 [1.38-5.68] and 2.53 [1.26-5.03], respectively), renal disease with cardiovascular disease (2.81 [1.32-6.01]), and diabetes with obesity (2.76 [1.39-5.45]).ConclusionsCo-occurrence of depressive symptoms, cognitive impairment, diabetes, or renal disease with other medical conditions substantially increases odds of frailty in older PWH. Identifying and treating these comorbidities may help to reduce functional decline with aging in PWH.

BACKGROUND: People with HIV (PWH) have increased frailty risk at younger ages compared with the general population. Multimorbidity is associated with frailty, yet effects of specific comorbidities on transition to frailty in PWH are unknown. SETTING: Prospective study of 219 PWH age 45 years or older in the National NeuroAIDS Tissue Consortium. METHODS: Frailty status was categorized using Fried frailty phenotype criteria. Comorbidities [bone disease, cardiovascular disease, cerebrovascular disease, liver disease, renal disease, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, obesity, cancers, neuropsychiatric conditions] were assessed from longitudinal data. Associations between baseline comorbidities and transition to frailty within 30 months were analyzed using Kaplan-Meier and Cox regression models. Grip strength was assessed using mixed-effects models. RESULTS: At baseline, the median age was 61 years, 73% were male 98% were on antiretroviral therapy, 29% had ≥3 comorbidities, 27% were robust, and 73% were pre-frail. Cerebrovascular disease, diabetes, and COPD were independent predictors of transition to frailty within 30 months in models adjusted for age, sex, and multimorbidity (≥3 additional comorbidities) [hazard ratios (95% confidence intervals) 2.52 (1.29 to 4.93), 2.31 (1.12 to 4.76), and 1.82 (0.95 to 3.48), respectively]. Furthermore, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity was associated with substantially increased frailty hazards compared with multimorbidity alone (hazard ratios 4.75-7.46). Cerebrovascular disease was associated with decreased baseline grip strength (P = 0.0001), whereas multimorbidity, diabetes, and COPD were associated with declining grip strength (P < 0.10). CONCLUSIONS: In older PWH, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity is associated with substantially increased risk of becoming frail within 30 months. Interventions targeting these comorbidities may ameliorate frailty and age-related functional decline in PWH.

Objective Abnormal deposition of the antimicrobial peptide amyloid beta (Aβ) is a characteristic of Alzheimer's Disease (AD). The objective of this study was to elucidate risk factors for brain Aβ in a cohort enriched for human immunodeficiency virus (HIV) and other neurotropic pathogens. Design Cross-sectional cohort study. Methods We examined autopsy brains of 257 donors with a mean age of 52.8 years; 62% were male; and 194 were HIV+ and 63 HIV-. Hyperphosphorylated tau (p-tau) and Aβ were identified in frontal and temporal regions by immunohistochemistry. APOE genotyping was performed. Clinical and neuropathological predictors for Aβ were identified in univariate analyses, and then tested in multivariate regressions. Results Cortical Aβ was identified in 32% of the sample, and active brain infection in 27%. Increased odds of Aβ were seen with increasing age and having an APOE e4 allele; for the overall sample, HIV+ status was protective and brain infection was not a predictor. Within the HIV+ population, predictors for Aβ were duration of HIV disease and APOE alleles, but not age. When HIV disease duration and other HIV parameters were introduced into models for the entire sample, HIV disease duration was equivalent to age as a predictor of Aβ. Conclusion We hypothesize that dual aspects of immune suppression and stimulation in HIV, and beneficial survivor effects in older HIV+ individuals, account for HIV+ status decreasing, and HIV duration increasing, odds of Aβ. Importantly, with HIV, disease duration replaces age as an independent risk for Aβ, suggesting HIV-associated accelerated brain senescence.

We characterized mechanisms of CNS viral reservoir establishment/replenishment using peripheral blood mononuclear cells (PBMC) of PLWH on cART and propose therapeutic targets to reduce/block selective entry of cells harboring HIV (HIV+) into the CNS. Using DNA/RNAscope, we show that CD14+ CD16+ monocytes with integrated HIV, transcriptionally active, and/or with active viral replication from PBMC of PLWH prescribed cART and virally suppressed, selectively transmigrate across a human BBB model., The human immunodeficiency virus (HIV) enters the central nervous system (CNS) within a few days after primary infection, establishing viral reservoirs that persist even with combined antiretroviral therapy (cART). We show that monocytes from people living with HIV (PLWH) on suppressive cART harboring integrated HIV, viral mRNA, and/or viral proteins preferentially transmigrate across the blood-brain barrier (BBB) to CCL2 and are significantly enriched post-transmigration, and even more highly enriched posttransmigration than T cells with similar properties. Using HIV-infected ART-treated mature monocytes cultured in vitro, we recapitulate these findings and demonstrate that HIV+ CD14+ CD16+ ART-treated monocytes also preferentially transmigrate. Cenicriviroc and anti-JAM-A and anti-ALCAM antibodies significantly and preferentially reduce/block transmigration of HIV+ CD14+ CD16+ ART-treated monocytes. These findings highlight the importance of monocytes in CNS HIV reservoirs and suggest targets to eliminate their formation and reseeding.

Background: Marijuana smoke contains some of the same toxicants present in tobacco smoke. Marijuana smoking is prevalent among HIV+ individuals, but few studies have characterized smoke-related toxicants or associated health outcomes in exclusive marijuana users. Methods: This longitudinal study included 245 participants over age 40 (76% HIV+). 33 plasma and 28 urine metabolites of nicotine, ∆-9-trans-tetrahydrocannabinol, polycyclic aromatic hydrocarbons, and volatile organic compounds were assayed by liquid or gas chromatography/mass spectrometry. Exposures and health outcomes were assessed from surveys and medical records. Findings: At baseline, 18% of participants were marijuana-only smokers, 20% tobacco-only smokers, and 24% dual marijuana-tobacco smokers (median (IQR) age 53 (47–60) years, 78% male, 54% white race). Marijuana smoking was independently associated with elevated plasma naphthalenes, 2-hydroxyfluorene sulfate, 4-vinylphenol sulfate, and o-cresol sulfate (p

Background Mental health consequences of the COVID-19 pandemic have been observed. Psychiatric symptoms in people living with HIV, and their relationship to physical symptomatology and prior psychopathology, are not yet reported. Setting An HIV cohort sheltering-in-place in New York City. Methods Forty-nine participants in a longitudinal study were contacted by telephone in April 2020. A structured interview queried COVID-19-associated physical symptoms, and mental health screens were performed with the generalized anxiety disorder-2 (GAD-2) and patient health questionnaire-2 (PHQ-2). Prior medical and neuropsychiatric data were obtained from preceding study visits. Post-hoc analyses were performed. Results The mean age of respondents was 62.1 years, 39% were women, and 35% African American, 37% Latinx, and 28% Caucasian. COVID-19-indicator symptoms were present in 69%; 41% had respiratory and 61% extra-pulmonary symptoms. Mental health symptoms were endorsed in 45% with PHQ-2 and 43% with GAD-2, although threshold for major depression was met in only 4% and for GAD in 14%. Higher PHQ scores were associated with respiratory symptoms, but not prior mood or anxiety disorders. GAD-2 scores were higher with past mood disorders, but not with prior anxiety disorders or respiratory symptoms. Conclusions Physical symptoms were frequent and mild psychiatric symptoms were common, but serious anxiety and depression were not often endorsed by this group of people living with HIV at the acute height of the New York City COVID-19 pandemic. Reasons for this are unclear, as this preliminary report is descriptive in nature. Short- and long-term consequences of acute mental health symptoms require further study.

Author(s): Ellis, Ronald J; Letendre, Scott L; Atkinson, J Hampton; Clifford, David; Collier, Ann C; Gelman, Benjamin B; Marra, Christina; McCutchan, J Allen; Morgello, Susan; Sacktor, Ned; Tang, Bin; Heaton, Robert K | Abstract: Background and objectivesPeople with HIV (PWH) often suffer from depressive symptoms which have a deleterious impact on numerous domains including antiretroviral adherence and quality of life. In the general population, a treatment-resistant phenotype of depression is associated with systemic inflammation, which is of considerable importance as it responds favorably to anti-inflammatory medications. Aging PWH experience increasing inflammation. We sought to evaluate the impact of chronic inflammation in aging PWH on depressed mood.MethodsPWH were recruited at 6 U.S. academic medical centers. Depressed mood was assessed using the Beck Depression Inventory (BDI)-II. Inflammatory biomarkers measured at the 12-year follow-up visit in blood plasma using immunoassays were neopterin, sTNFRII, d-dimer, IL-6, CRP, MCP-1, sCD14 and sCD40L. Factor analyses with oblique Equamax rotation were employed to reduce the dimensionality of the biomarkers.ResultsParticipants were 78 PWH, 14 (17.9%) women, 40 (51.3%) non-White, mean age 55.3 (±SD 8.29), with a nadir and current CD4 of 134 (IQR 36, 204) and 567 (316, 797), respectively. 80.5% were virally suppressed. A factor analysis of the eight inflammatory biomarkers in plasma at the 12-year follow-up visit yielded 3 Factors, with Factor 1 loading on neopterin and sTNFRII, Factor 2 loading on d-dimer, IL-6 and CRP, and Factor 3 loading on sCD40L (MCP-1 and sCD14 did not appear in any of the factors). Univariate regressions of each factor vs BDI-II scores yielded significance only for Factor 2 (rn​=n​0.295; pn​=n​0.0083 (Bonferroni-adjusted pn​=n​0.0261). Of the Factor 2 component biomarkers, BDI-II scores correlated significantly with d-dimer and IL-6, but not CRP. Women had worse BDI-II scores (pn​=n​0.0127). In a logistic regression with sex and Factor 2, both variables were significant (sex pn​=n​0.0246, Factor 2 pn​=n​0.0168). The relationship between Factor 2 and BDI was significant for men (rn​=n​0.348 [95% CI 0.111, 0.547]; pn​=n​0.0049), but not women (rn​=n​0.0580 95% CI -0.488, 0.571]; pn​=n​0.844). Viral suppression was not significant in the multivariate model.ConclusionsSome PWH with depressed mood have elevated markers of inflammation in blood. Men showed this relationship, while women did not. Together with previous findings that an inflammatory depression phenotype responds to treatment with anti-inflammatory medications, our findings suggest that treatment with anti-inflammatory medications might benefit at least a subset of depressed PWH who have a high inflammatory biomarker profile, as well as poor response to antidepressant medications alone, and that the pathophysiology of depression in men and women with HIV may differ.

Introduction The diagnosis of IRIS is based on evidence of clinical worsening and immune reconstitution in the setting of combined antiretroviral therapy (cART) initiation. While central nervous system IRIS (CNS IRIS) is thought to be prevalent in resource limited settings (RLS), its identification is constrained by limited data on pre-treatment HIV disease and diagnostic testing. A diagnosis can be improved with neuroimaging and cerebrospinal fluid (CSF) studies, which are not universally available in RLS. This study evaluated whether diagnoses of CNS IRIS could be achieved in a resource limited setting based on established criteria. Methods A retrospective chart review of HIV+ individuals, on ARVs at the time of presentation in two cohort studies of suspected CNS opportunistic infection or tuberculous (TB) meningitis who were admitted to a tertiary care facility in Lusaka, Zambia. Results Using currently validated criteria, none of the 254 participants evaluated could be diagnosed with CNS IRIS, as there was no information on post-treatment trajectory of HIV viral loads or CD4 counts. Only one participant had a definitive, non-IRIS infectious diagnosis based on comprehensive testing. Of the remaining 253 patients, 68 (27%) had an identified potential CNS pathogen, 92 (36%) had inflammatory CSF in the absence of a pathogen, and 94 (37%) had normal CSF despite presenting with CNS symptoms. Conclusion The absence of HIV disease trajectory data, and lack of comprehensive diagnostic testing, compounded by a high prevalence of infectious pathogens, substantially limits the ability to diagnose CNS IRIS in RLS.

Coronavirus disease 2019 (COVID-19) is a pandemic disease currently affecting millions of people worldwide. Its neurological implications are poorly understood, and further study is urgently required. A hypercoagulable state has been reported in patients with severe COVID-19, but nothing is known about coagulopathy in patients with milder disease. We describe cases of patients in New York City presenting with stroke secondary to large vessel thrombosis without occlusion, incidentally found to have COVID-19 with only mild respiratory symptoms. This is in contrast to the venous thrombosis and microangiopathy that has been reported in patients with severe COVID-19. Our cases suggest that even in the absence of severe disease, patients with COVID-19 may be at increased risk of thrombus formation leading to stroke, perhaps resulting from viral involvement of the endothelium. Further systematic study is needed because this may have implications for primary and secondary stroke prevention in patients with COVID-19.

BACKGROUND: In clinical practice, calcifications seen on CT studies within the large brain arteries are often referred as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exists to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the Circle of Willis in an autopsy based sample. METHODS: We carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and non-atherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA. RESULTS: In univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% v. 14%, p

Objective: The relationship of cerebrospinal fluid (CSF) extracellular vesicles to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF extracellular vesicles and their association with central nervous system (CNS) injury related biomarkers [neurofilament light (NFL), S100B, neopterin] and NCI in HIV-positive individuals on combination antiretroviral therapy (cART). Design: A cross-sectional and longitudinal study of CSF samples from HIV-positive individuals on cART. Methods: NFL, S100B and neopterin were measured by ELISA in 190 CSF samples from 112 individuals (67 HIV-positive and 45 HIV-negative). CSF extracellular vesicles were isolated and characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting for exosome markers (CD9, CD63, CD81, FLOT-1) and ELISA for HLA-DR. Results: HIV-positive individuals had median age 52 years, 67% with suppressed plasma viral load (< 50 copies/ml), median CD4+ nadir 66 cells/μl and CD4+ cell count 313 cells/μl. CSF NFL, S100B and neopterin levels were higher in HIV-positive vs. HIV-negative individuals, and nonsuppressed vs. suppressed HIV-positive individuals. Although CSF NFL and S100B levels were higher in NCI vs. unimpaired HIV-positive individuals (P

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

Objective To test whether HIV is associated with brain large artery vulnerable intima. Design Cross-sectional study of autopsied HIV-positive (HIV+) cases sex and age-matched to HIV-negative (HIV-) controls. Methods Brain large arteries from 302 autopsied cases (50% HIV+) were evaluated morphometrically for the presence of atherosclerosis, size of necrotic core, and fibrous cap thickness. Intima vulnerability was measured as intima elastolytic score [0-5, based on intimal metalloproteinases (MMP)-2, MMP-3, and MMP-9, and tissue inhibitor for MMP-1 and MMP-2 staining], intima inflammatory score (0-3, based on intimal presence of CD3 and CD68 cells and TNF-α staining), neoangiogenesis (factor VIII staining), and apoptosis (caspase 3 staining). Hierarchical generalized linear models were used to obtain the beta estimates and their 95% confidence intervals, adjusting for demographics and vascular risk factors. Results The prevalence of atherosclerosis did not differ by HIV status. Necrotic cores filled larger proportions of the intima in HIV+ individuals with CD4 cell count above 200 cells/μl at death compared to HIV- controls (adjusted B = 11.6%, P = 0.04). HIV+ individuals had greater elastolytic scores (adjusted B = 0.34, P = 0.02), especially those with less than 200 CD4 cells/μl at death (adjusted B = 0.41, P = 0.01). Intima inflammation, neoangiogenesis, and apoptosis were not different among HIV+ cases versus HIV- controls. Conclusion Individuals with HIV and CD4 cell count at least 200 cells/μl at death had relatively larger necrotic cores, whereas those with HIV and CD4 cell count below 200 cells/μl at death had evidence of increased connective tissue remodeling in the intima. These findings suggest an increased potential for endothelial erosion, thrombosis, and plaque rupture that may relate to higher risk for vascular events.

Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p= 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p= 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p= 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p= 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p&nbsp

HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14(+)CD16(+) monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14(+)CD16(+) monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14(+)CD16(+) monocytes with cognitive status, proton magnetic resonance spectroscopy ((1)H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14(+)CD16(+) monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14(+)CD16(+) monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r(2) = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r(2) = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14(+)CD16(+) monocytes also correlated with PBMC HIV DNA copies (ρ = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14(+)CD16(+) monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14(+)CD16(+) monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND.

Exosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes were characterized by electron microscopy, nanoparticle tracking, immunoblotting, and LC-MS/MS proteomics. Plasma exosomes were increased in HIV-positive subjects compared to controls, and correlated with increased oxidative stress markers (cystine, oxidized cys-gly) and decreased PUFA (DHA, EPA, DPA). Untargeted proteomics detected markers of exosomes (CD9, CD63, CD81), immune activation (CD14, CRP, HLA-A, HLA-B), oxidative stress (CAT, PRDX1, PRDX2, TXN), and Notch4 in plasma exosomes. Exosomal Notch4 was increased in HIV-positive subjects versus controls and correlated with immune activation markers. Treatment of THP-1 monocytic cells with patient-derived exosomes induced expression of genes related to interferon responses and immune activation. These results suggest that exosomes in ART-treated HIV patients carry proteins related to immune activation and oxidative stress, have immunomodulatory effects on myeloid cells, and may have pro-inflammatory and redox effects during pathogenesis.

HIV-associated neurocognitive disorders (HAND) remain prevalent in the combined antiretroviral therapy (CART) era, especially the milder forms. Despite these milder phenotypes, we have shown that motor abnormalities persist and have quantified them with the HIV Dementia Motor Scale (HDMS). Our objectives were to replicate, in an independent sample, our prior findings that the HDMS is associated with cognitive impairment in HIV, while adding consideration of age-associated comorbidities such as cerebrovascular disease, and to examine the longitudinal trajectories of cognitive and motor dysfunction. We included all participants enrolled in the Manhattan HIV Brain Bank (MHBB) from January 2007 to May 2017 who had complete baseline data (N = 164). MHBB participants undergo standardized longitudinal assessments including documentation of comorbidities and medications, blood work, the HDMS, and neurocognitive testing. We found that motor dysfunction, cognitive impairment, and cerebrovascular disease were significantly associated with each other at baseline. Cerebrovascular disease independently predicted cognitive impairment in a multivariable model. Longitudinal analysis in a subset of 78 participants with ≥ 4 years of follow-up showed a stable cognition but declining motor function. We conclude that the HDMS is a valid measurement of motor dysfunction in HIV-infected patients and is associated with cognitive impairment and the presence of cerebrovascular disease. Cognitive impairment is mild and stable in CART-treated HIV; however, motor function declines over time, which may be related to the accrual of comorbidities such as cerebrovascular disease. Further research should examine the mechanisms underlying motor dysfunction in HIV and its clinical impact.

Protease inhibitors were independent predictors of cerebrospinal fluid (CSF) escape in antiretroviral therapy (ART)–experienced human immunodeficiency virus–infected adults. M184V/I combined with thymidine analog mutations were more frequent in adults with CSF escape compared to no escape. These findings suggest optimizing ART may reduce likelihood of CSF escape., Background Cerebrospinal fluid (CSF) viral escape occurs in 4%–20% of human immunodeficiency virus (HIV)–infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. Methods A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models. Results Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/μL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8–5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score–adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (

Objective CD16+ /CD163+ macrophages (MΦs) and microglia accumulate in the brains of patients with human immunodeficiency virus (HIV) encephalitis (HIVE), a neuropathological correlate of the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia. Recently, we found that some parenchymal microglia in brain of HIV+ subjects without encephalitis (HIV/noE) but with varying degrees of neurocognitive impairment express CD16 and CD163, even in the absence of detectable virus production. To further our understanding of microglial activation in HIV, we investigated expression of specific genes by profiling parenchymal microglia from archival brain tissue of patients with HIVE and HIV/noE, and HIV- controls. Methods Single-population microarray analyses were performed on ∼2,500 laser capture microdissected CD163+ , CD16+ , or CD68+ MΦs/microglia per case, using terminal continuation RNA amplification and a custom-designed array platform. Results Several classes of microglial transcripts in HIVE and HIV/noE were altered, relative to HIV- subjects, including factors related to cell stress, immune activation, and apoptosis. Additionally, several neurotrophic factors were reduced in HIV infection, suggesting an additional mechanism of neuropathogenesis. The majority of transcripts altered in HIVE displayed intermediate changes in HIV/noE. Interpretation Our results support the notion that microglia contribute to the maintenance of brain homeostasis and their potential loss of function in the context of chronic inflammation contributes to neuropathogenesis. Furthermore, they indicate the utility of profiling MΦs/microglia to increase our understanding of microglia function, as well as to ascertain alterations in specific pathways, genes, and potentially, encoded proteins that may be amenable to targeted treatment modalities in diseases affecting the brain. Ann Neurol 2018;83:406-417.

We aimed to test the hypothesis that brain large artery diameters relate to distal downstream arteriolar diameters. In a sample of 110 autopsied individuals (69% men, 76% HIV+, mean age 51), we used multilevel models to relate large artery lumen and lumen-to-wall ratio to left frontal lobe arteriolar lumen and lumen-to-wall ratio adjusting for demographics and vascular risk factors. Comparing the large artery characteristics of the whole brain did not disclose significant associations with frontal lobe arteriolar characteristics. However, restricting the comparison to large arteries upstream of the studied arterioles demonstrated an independent association between left-sided frontal lobe arteriolar luminal diameter with large artery luminal diameters (B = 1.82 ± 0.77, P = 0.01) and with large artery lumen-to-wall ratio (B = 0.58 ± 0.29, P = 0.05). In stratified models, the point estimates in the HIV+ subsample were larger than in the HIV- subsample. These finding suggest coupling between higher proximal blood flow represented by large artery diameter and lower distal resistance represented by arteriolar dilatation. The relationship between arteriolar dilatation and brain parenchyma homeostasis should be further studied.

CD14+CD16+ monocytes transmigrate into the CNS of HIV-positive people in response to chemokines elevated in the brains of infected individuals, including CXCL12. Entry of these cells leads to viral reservoirs, neuroinflammation, and neuronal damage. These may eventually lead to HIV-associated neurocognitive disorders. Although antiretroviral therapy (ART) has significantly improved the lives of HIV-infected people, the prevalence of cognitive deficits remains unchanged despite ART, still affecting >50% of infected individuals. There are no therapies to reduce these deficits or to prevent CNS entry of CD14+CD16+ monocytes. The goal of this study was to determine whether CXCR7, a receptor for CXCL12, is expressed on CD14+CD16+ monocytes and whether a small molecule CXCR7 antagonist (CCX771) can prevent CD14+CD16+ monocyte transmigration into the CNS. We showed for the first time that CXCR7 is on CD14+CD16+ monocytes and that it may be a therapeutic target to reduce their entry into the brain. We demonstrated that CD14+CD16+ monocytes and not the more abundant CD14+CD16− monocytes or T cells transmigrate to low homeostatic levels of CXCL12. This may be a result of increased CXCR7 on CD14+CD16+ monocytes. We showed that CCX771 reduced transmigration of CD14+CD16+ monocytes but not of CD14+CD16− monocytes from uninfected and HIV-infected individuals and that it reduced CXCL12-mediated chemotaxis of CD14+CD16+ monocytes. We propose that CXCR7 is a therapeutic target on CD14+CD16+ monocytes to limit their CNS entry, thereby reducing neuroinflammation, neuronal damage, and HIV-associated neurocognitive disorders. Our data also suggest that CCX771 may reduce CD14+CD16+ monocyte-mediated inflammation in other disorders.

BACKGROUND AND PURPOSE Human immunodeficiency virus (HIV)-infected patients commonly have abnormalities in cerebral white matter that are visible on magnetic resonance imaging (MRI) as hyperintensities (WMHs). Visual rating scales (VRSs) have been used to quantify WMH in other diseases such as cerebral small vessel disease (CSVD), but not in HIV. Such scales are advantageous because they are applicable to routinely acquired MRIs and so are suitable for large-scale studies and clinical care. We sought to establish the utility of three VRSs (the Fazekas, Scheltens, and van Sweiten scales) in HIV. METHODS The Manhattan HIV Brain Bank (MHBB) is a longitudinal cohort study that performs serial neurologic examinations and neuropsychological testing. All brain MRIs (n = 73) performed for clinical purposes on MHBB participants were scored using the three VRSs. We assessed reliability, validity, and correlation of the VRS with clinical factors relevant to HIV and CSVD. RESULTS The VRSs all showed acceptable internal consistency and interrater reliability and were highly correlated with one another (r = 0.836-0.916, P < .001). The Fazekas and Scheltens scales demonstrated more WMH in periventricular regions, and the Scheltens scale also suggested a frontal to occipital gradient, with greater WMH frontally. All three VRSs correlated significantly with cognitive impairment (global T score). Age and hepatitis C virus antibody serostatus were the strongest clinical/demographic correlates of WMH, followed by African-American race. CONCLUSIONS VRSs reliably quantify WMH in HIV-infected individuals and correlate with cognitive impairment. Future studies may find routinely acquired brain MRI quantified by VRS to be an accessible and meaningful neurologic outcome measure in HIV.

Supplemental Digital Content is Available in the Text., Background: Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels. Methods: Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016. Results: Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm3 and CD4 nadir 21 cells/mm3. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51–999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA 15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

Background and Purpose— We tested the hypothesis that posterior brain arteries differ pathologically from anterior brain arteries and that this difference varies with age. Methods— Brain large arteries from 194 autopsied individuals (mean age 56±17 years, 63% men, 25% nonwhite, 17% with brain infarcts) were analyzed to obtain the areas of arterial layers and lumen as well as the relative content of elastin, collagen, and amyloid. Visual rating was used to determine the prevalence of atheroma, calcification, vasa vasorum , pattern of intima thickening, and internal elastic lamina gaps. We used multilevel models adjusting for age, sex, ethnicity, vascular risk factors, artery type and location, and multiple comparisons. Results— Of 1362 large artery segments, 5% had vasa vasorum, 5% had calcifications, 15% had concentric intimal thickening, and 11% had atheromas. Posterior brain arteries had thinner walls, less elastin, and more concentric intima thickening than anterior brain arteries. Compared to anterior brain arteries, the basilar artery had higher arterial area encircled by the internal elastic lamina, whereas the vertebral arteries had higher prevalence of elastin loss, concentric intima thickening, and nonatherosclerotic stenosis. In younger individuals, vertebral artery calcifications were more likely than calcification in anterior brain arteries, but this difference attenuated with age. Conclusions— Posterior brain arteries differ pathologically from anterior brain arteries in the degree of wall thickening, elastin loss, and concentric intimal thickening.

BackgroundExtracellular vesicles (EVs) are nano-sized particles present in most body fluids including cerebrospinal fluid (CSF). Little is known about CSF EV proteins in HIV+ individuals. Here, we characterize the CSF EV proteome in HIV+ subjects and its relationship to neuroinflammation, stress responses, and HIV-associated neurocognitive disorders (HAND).MethodsCSF EVs isolated from 20 HIV+ subjects with (n = 10) or without (n = 10) cognitive impairment were characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting, and untargeted LC/MS/MS mass spectrometry. Functional annotation was performed by gene ontology (GO) mapping and expression annotation using Biobase Transfac and PANTHER software. Cultured astrocytic U87 cells were treated with hydrogen peroxide for 4 h to induce oxidative stress and EVs isolated by ultracentrifugation. Selected markers of astrocytes (GFAP, GLUL), inflammation (CRP), and stress responses (PRDX2, PARK7, HSP70) were evaluated in EVs released by U87 cells following induction of oxidative stress and in CSF EVs from HIV+ patients by immunoblotting.ResultsMass spectrometry identified 2727 and 1626 proteins in EV fractions and EV-depleted CSF samples, respectively. CSF EV fractions were enriched with exosomal markers including Alix, syntenin, tetraspanins, and heat-shock proteins and a subset of neuronal, astrocyte, oligodendrocyte, and choroid plexus markers, in comparison to EV-depleted CSF. Proteins related to synapses, immune/inflammatory responses, stress responses, metabolic processes, mitochondrial functions, and blood-brain barrier were also identified in CSF EV fractions by GO mapping. HAND subjects had higher abundance of CSF EVs and proteins mapping to GO terms for synapses, glial cells, inflammation, and stress responses compared to those without HAND. GFAP, GLUL, CRP, PRDX2, PARK7, and HSP70 were confirmed by immunoblotting of CSF EVs from subjects with HAND and were also detected in EVs released by U87 cells under oxidative stress.ConclusionsThese findings suggest that CSF EVs derived from neurons, glial cells, and choroid plexus carry synaptic, immune/inflammation-related, and stress response proteins in HIV+ individuals with cognitive impairment, representing a valuable source for biomarker discovery.

We describe a case of primary neurolymphomatosis (PNL) with unusual presentation of a right lumbosacral polyradiculoneuropathy with no other lesions shown on the whole body fludeoxyglucose-positron emission tomography (FDG-PET) scan. A right superficial peroneal nerve lesion biopsy revealed infiltration of the nerve by malignant CD20+ lymphoma cells. The lymphoma cells expressed Bcl-2 but not CD10, suggesting an origin in peripheral blood not lymph nodes. The patient responded very well to the combined radiotherapy and chemotherapy with the R-MPV (rituximab, methotrexate, procarbazine, and vincristine) regimen. The patient showed marked clinical improvement and complete resolution of lymphoma lesions on the PET scan.