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The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

Purpose of reviewCannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV.Recent findingsResults revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

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) 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

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02-0.29; FTL-by-sex βinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = -0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178-448) and 643 (502-839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42-21.00], and 15.16 [1.07-215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration.

ObjectiveMethamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.Method423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.ResultsGlobally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.ConclusionsOur findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.

Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50-84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology-this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.

BackgroundPersons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex.MethodsSix plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities.ResultsParticipants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C-C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (β = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (β = -3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected.InterpretationWe identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

HIV reservoirs persist in anatomic compartments despite antiretroviral therapy (ART). Characterizing archival HIV DNA in the central nervous system (CNS) and other tissues is crucial to inform cure strategies. We evaluated paired autopsy brain-frontal cortex (FC), occipital cortex (OCC), and basal ganglia (BG)-and peripheral lymphoid tissues from 63 people with HIV. Participants passed away while virally suppressed on ART at the last visit and without evidence of CNS opportunistic disease. We quantified total HIV DNA in all participants and obtained full-length HIV-envelope (FL HIV-env) sequences from a subset of 14 participants. We detected HIV DNA (gag) in most brain (65.1%) and all lymphoid tissues. Lymphoid tissues had higher HIV DNA levels than the brain (P  0.2), while OCC had the lowest levels (P = 0.01). Females had higher HIV DNA levels in tissues than males (gag, P = 0.03; 2-LTR, P = 0.05), suggesting possible sex-associated mechanisms for HIV reservoir persistence. Most FL HIV-env sequences (n = 143) were intact, while 42 were defective. Clonal sequences were found in 8 out of 14 participants, and 1 participant had clonal defective sequences in the brain and spleen, suggestive of cell migration. From 10 donors with paired brain and lymphoid sequences, we observed evidence of compartmentalized sequences in 2 donors. Our data further the idea that the brain is a site for archival HIV DNA during ART where compartmentalized provirus may occur in a subset of people. Future studies assessing FL HIV-provirus and replication competence are needed to further evaluate the HIV reservoirs in tissues. IMPORTANCE HIV infection of the brain is associated with adverse neuropsychiatric outcomes, despite efficient antiretroviral treatment. HIV may persist in reservoirs in the brain and other tissues, which can seed virus replication if treatment is interrupted, representing a major challenge to cure HIV. We evaluated reservoirs and genetic features in postmortem brain and lymphoid tissues from people with HIV who passed away during suppressed HIV replication. We found a differential distribution of HIV reservoirs across brain regions which was lower than that in lymphoid tissues. We observed that most HIV reservoirs in tissues had intact envelope sequences, suggesting they could potentially generate replicative viruses. We found that women had higher HIV reservoir levels in brain and lymphoid tissues than men, suggesting possible sex-based mechanisms of maintenance of HIV reservoirs in tissues, warranting further investigation. Characterizing the archival HIV DNA in tissues is important to inform future HIV cure strategies.

CD14++CD16+ monocytes are susceptible to HIV-1 infection, and cross the blood-brain barrier. HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared to HIV-1B, which might influence monocyte trafficking into the CNS. We hypothesized that the proportion of monocytes in CSF in HIV-1C is lower than HIV-1B group. We sought to assess differences in monocyte proportions in cerebrospinal fluid (CSF) and peripheral blood (PB) between people with HIV (PWH) and without HIV (PWoH), and by HIV-1B and -C subtypes. Immunophenotyping was performed by flow cytometry, monocytes were analyzed within CD45 + and CD64 + gated regions and classified in classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14lowCD16+). Among PWH, the median [IQR] CD4 nadir was 219 [32-531] cell/mm3; plasma HIV RNA (log10) was 1.60 [1.60-3.21], and 68% were on antiretroviral therapy (ART). Participants with HIV-1C and -B were comparable in terms of age, duration of infection, CD4 nadir, plasma HIV RNA, and ART. The proportion of CSF CD14++CD16+ monocytes was higher in participants with HIV-1C than those with HIV-1B [2.00(0.00-2.80) vs. 0.00(0.00-0.60) respectively, p = 0.03 after BH correction p = 0.10]. Despite viral suppression, the proportion of total monocytes in PB increased in PWH, due to the increase in CD14++CD16+ and CD14lowCD16+ monocytes. The HIV-1C Tat substitution (C30S31) did not interfere with the migration of CD14++CD16+ monocytes to the CNS. This is the first study to evaluate these monocytes in the CSF and PB and compare their proportions according to HIV subtype.

BackgroundThe health status of people with HIV (PWH) influences their health-related quality of life (HRQOL). Modifiable lifestyle factors may improve HRQOL. This study (1) explores the association between modifiable lifestyle factors (physical activity and nutrition) and HRQOL and (2) examines if these lifestyle factors moderate the association health status and HRQOL.MethodsParticipants included 91 community dwelling PWH (age 36-65 years) from the university lab. Participants reported mental and physical HRQOL via the Medical Outcome Study 36-Item Short-Form (SF-36). Physical activity was examined via the International Physical Activity Questionnaire and nutrition (i.e., fruit and vegetable consumption) was assessed with the By-Meal Screener. Health status was ascertained via the Veterans Aging Cohort Study (VACS) Index.ResultsAim 1 analyses indicated that neither physical activity nor nutrition was related to mental HRQOL (p's > .05). However, greater physical activity (β = .33, p  .05).ConclusionPhysical HRQOL is related to self-reported physical activity and nutrition, with nutrition showing a moderating effect on the association between health status and physical HRQOL. Thus, future interventional studies designed to improve physical HRQOL should target both physical activity and nutrition.

BackgroundAnemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain.MethodsParticipants included 1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression.ResultsThe mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05).ConclusionsAnemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.

The transactivator of transcription (Tat) is a HIV regulatory protein which promotes viral replication and chemotaxis. HIV-1 shows extensive genetic diversity, HIV-1 subtype C being the most dominant subtype in the world. Our hypothesis is the frequency of CSF CD3+CD56+ and CD3-CD56dim is reduced in HIV-1C compared to HIV-1B due to the Tat C30S31 substitution in HIV-1C. 34 CSF and paired blood samples (PWH, n = 20; PWoH, n = 14) were studied. In PWH, the percentage of CD3+CD56+ was higher in CSF than in blood (p

BackgroundNeurofilament 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).MethodsCohort 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.ResultsCohort 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.ConclusionsBoth 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.

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 (

BackgroundConflicting evidence exists on the impact of cannabis use on antiretroviral therapy (ART) adherence among people with human immunodeficiency virus (PWH). We leveraged data collected among older PWH to characterize longitudinal associations between cannabis use and ART adherence.MethodsAIDS Clinical Trials Group (ACTG) A5322 study participants were categorized as

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

BackgroundHIV infection causes neuroinflammation and immune activation (NIIA) and systemic inflammation and immune activation (SIIA), which in turn drive neurodegeneration (ND). Cross-sectionally, higher levels of NIIA biomarkers correlate with increased biomarkers of ND. A more convincing confirmation would be a longitudinal demonstration.MethodsPWH in the US multisite CHARTER Aging project were assessed at a baseline visit and after 12 years using standardized evaluations. We measured a panel of 14 biomarkers of NIIA, SIIA, and ND in plasma and CSF at two time points and calculated changes from baseline to the 12-year visit. Factor analysis yielded simplified indices of NIIA, SIIA, and ND.ResultsThe CSF NIIA factor analysis yielded Factor1 loading on soluble tumor necrosis factor type-2 (sTNFR-II) and neopterin, and Factor2, loading on MCP1, soluble CD14, and IL-6. The SIIA factor analysis yielded Factor1 loading on CRP, D-dimer, and Neopterin; Factor2 loading on sTNFR-II. The ND analysis yielded Factor1 loading on Phosphorylated tau (p-tau) and Aβ42; Factor2 loading on NFL. NIIA Factor1, but not Factor2, correlated with increases in CSF NFL (r = 0.370, p = 0.0002).ConclusionsIncreases in NIIA and SIIA in PWH were associated with corresponding increases in ND, suggesting that reducing neuro/systemic inflammation might slow or reverse neurodegeneration.

Inter-individual differences in the gut microbiome are linked to alterations in inflammation and blood-brain barrier permeability, which may increase the risk of depression in people with HIV (PWH). The microbiome profile of blood, which is considered by many to be typically sterile, remains largely unexplored. We aimed to characterize the blood plasma microbiome composition and assess its association with major depressive disorder (MDD) in PWH and people without HIV (PWoH). In this cross-sectional, observational cohort, we used shallow-shotgun metagenomic sequencing to characterize the plasma microbiome of 151 participants (84 PWH and 67 PWoH), all of whom underwent a comprehensive neuropsychiatric assessment. The microbial composition did not differ between PWH and PWoH or between participants with MDD and those without it. Using the songbird model, we computed the log ratio of the highest and lowest 30% of the ranked classes associated with HIV and MDD. We found that HIV infection and lifetime MDD were enriched in a set of differentially abundant inflammatory classes, such as Flavobacteria and Nitrospira. Our results suggest that the circulating plasma microbiome may increase the risk of MDD related to dysbiosis-induced inflammation in PWH. If confirmed, these findings may indicate new biological mechanisms that could be targeted to improve treatment of MDD in PWH.

We determined the prevalence of Alzheimer's disease (AD) pathological hallmarks, amyloid-β and phosphorylated-Tau, in autopsied brains of 49 people with HIV (PWH) (ages: 50-68; mean age = 57.0) from the National NeuroAIDS Tissue Consortium and in a comparative cohort of 55 people without HIV (PWoH) from the UC San Diego Alzheimer's Disease Research Center (17 controls, 14 mild cognitive impairment, 24 AD; ages: 70-102, mean age = 88.7). We examined how AD pathology relates to domain-specific cognitive functions in PWH overall and in sex-stratified samples. Amyloid-β and phosphorylated-Tau positivity (presence of pathology of any type/density) was determined via immunohistochemistry in AD-sensitive brain regions. Among PWH, amyloid-β positivity ranged from 19% (hippocampus) to 41% (frontal neocortex), and phosphorylated-Tau positivity ranged from 47% (entorhinal cortex) to 73% (transentorhinal cortex). Generally, AD pathology was significantly less prevalent, and less severe when present, in PWH versus PWoH regardless of cognitive status. Among PWH, positivity for AD pathology related most consistently to memory-related domains. Positivity for p-Tau pathology related to memory-related domains in women with HIV only, although the sample size of women with HIV was small (n = 10). Results indicate that AD pathology is present in a sizable portion of middle aged and older PWH, although not to the extent in older PWoH. Studies with better age-matched PWoH are needed to examine the effect of HIV status on AD pathology.

There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes' transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users' postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

ObjectiveMethamphetamine and cannabis are two widely used substances among people living with HIV (PLWH). Whereas methamphetamine use has been found to worsen HIV-associated neurocognitive impairment, the effects of combined cannabis and methamphetamine use disorder on neurocognition in PLWH are not understood. In the present study, we aimed to determine the influence of these substance use disorders on neurocognition in PLWH and to explore if methamphetamine-cannabis effects interacted with HIV status.Method and participantsAfter completing a comprehensive neurobehavioral assessment, PLWH (n = 472) were stratified by lifetime methamphetamine (M-/M+) and cannabis (C-/C+) DSM-IV abuse/dependence disorder into four groups: M-C- (n = 187), M-C+ (n = 68), M+C-, (n = 82), and M+C+ (n = 135). Group differences in global and domain neurocognitive performances and impairment were examined using multiple linear and logistic regression, respectively, while holding constant other covariates that were associated with study groups and/or cognition. Data from participants without HIV (n = 423) were added, and mixed-effect models were used to examine possible interactions between HIV and substance use disorders on neurocognition.ResultsCompared with M+C+, M+C- performed worse on measures of executive functions, learning, memory, and working memory and were more likely to be classified as impaired in those domains. M-C- performed better than M+C+ on measures of learning and memory but worse than M-C+ on measures of executive functions, learning, memory, and working memory. Detectable plasma HIV RNA and nadir CD4 < 200 were associated with lower overall neurocognitive performance, and these effects were greater for M+C+ compared with M-C-.ConclusionsIn PLWH, lifetime methamphetamine use disorder and both current and legacy markers of HIV disease severity are associated with worse neurocognitive outcomes. There was no evidence of an HIV × M+ interaction across groups, but neurocognition was most impacted by HIV among those with polysubstance use disorder (M+C+). Better performance by C+ groups is consistent with findings from preclinical studies that cannabis use may protect against methamphetamine's deleterious effects.

IntroductionAn unusual cluster of myoclonic epilepsy was observed in a Romanian pediatric HIV cohort concurrent with measles outbreaks. We describe this particular form of subacute measles encephalitis (SME) in a group of HIV-infected children and adolescents with severe immunosuppression.MethodsThis is a single-center study, starting in 1997 and covering 4 measles outbreaks in Romania. The presumptive diagnosis of subacute myoclonic measles encephalitis (SMME) was based on: (1) epidemiological data, previous measles episode or presumed contact with measles virus (MV), (2) clinical presentation with initial localized myoclonic jerks with rapid extension and subsequent motor deficit with preserved mental status, and (3) neuroimaging studies revealing cortical gray matter lesions. Definitive diagnosis was based on a neuropathological exam and immunohistochemistry of brain tissues, and measles RNA detection in the cerebrospinal fluid (CSF).ResultsThirty-six patients were diagnosed with a particular form of SME during consecutive measles outbreaks in Romania: 1996-1998 (22); 2005-2008 (12); 2010-2011 (1) and 2016-2018 (1). Most children were born in the late 80s and had parenterally acquired HIV infection in early childhood. Before the episode of SMME, 11 patients had confirmed measles, while the rest, without typical rash, had a respiratory tract infection and/or presumed previous measles contact. In all patients, the clinical onset was sudden, with unilateral myoclonus. MRI findings revealed mainly focal cortical gray matter lesions. Neurologic symptoms progressed rapidly to coma and death in most patients. Three patients survived SMME, they had higher CD4 count at onset, slower progression of neurological symptoms, and benefit of immune recovery with cART. Immunocytochemistry studies revealed MV in the brain with a pattern suggesting an ascending viral neural infection. MV was isolated from CSF in 7 out of 8 patients. Sequence analysis of MV RNA from both nasopharyngeal swabs and CSF was available for one patient with similar N-450 strain characteristics.ConclusionDuring an outbreak of measles, neurological manifestations, especially myoclonus in immunosuppressed patients, can be related to measles even in the absence of an acute episode. This particular form of subacute myoclonic measles encephalitis is an opportunistic fatal disease. Immune recovery due to effective antiretroviral treatment might increase survival.

The accumulation of soluble proteins and metabolites during wakefulness and their clearance during sleep via the glymphatic system occurs in healthy adults and is disturbed in some neurological conditions. Such diurnal variations in the cerebrospinal fluid (CSF) proteins produced outside the central nervous system and entering via the blood-brain barrier (BBB) have not been evaluated in people with HIV (PWH). CSF and blood were collected in 165 PWH at six US centers between 2003 and 2007. The time of collection was compared to CSF albumin, globulin, and total protein concentrations using bivariate and multivariate regression. Participants all took antiretroviral therapy (ART) and were mostly middle-aged (median age 44.0 years) men (78.8%), with AIDS (77.0%), plasma HIV RNA ≤ 200 copies/mL (75.8%), and immune recovery (median CD4+ T-cell count 414/µL). CSF was collected at median 1:10 p.m. (range 9:00 a.m. to 5:20 p.m.) and within a median of 15 min of blood collection. A later time of CSF collection was associated with higher total protein (p = 0.0077) and albumin (p = 0.057) in CSF but not in serum, and was additionally associated with higher CSF globulin (p = 0.013). The glymphatic clearance of albumin, globulin, and total protein is preserved in PWH. The analyses of soluble biomarkers in CSF should account for the time of collection.

ObjectiveChronic inflammation and vascular dysfunction (e.g., chronic endothelial activation) are related yet dissociable mechanisms of HIV-associated neurocognitive impairment (NCI), even among those on antiretroviral therapy (ART). However, how these mechanisms differentially contribute to domain-specific deficits in people with and without HIV (PWH, PWoH) is unclear. We empirically-derived profiles of NCI and examined relationships with peripheral inflammatory and vascular biomarkers.MethodsParticipants were 84 virally-suppressed PWH and 126 PWoH who underwent neuropsychological testing and blood draw. Cluster analysis identified subgroups based on domain deficit scores. ANOVAs examined HIV serostatus and cluster group differences in composite plasma biomarker z-scores of inflammation (IL-6, CXCL10/IP-10, CCL2/MCP-1) and vascular injury (VCAM-1, ICAM-1, uPAR). Confirmatory regressions examined the interaction of HIV and biomarker z-scores on domain-specific T-scores, controlling for cardiovascular disease (CVD) risk and psychosocial factors.ResultsCluster analysis identified three groups: Unimpaired (n = 129), Learning/Recall (n = 52, isolated learning/recall deficits), Dysexecutive/Slow (n = 29, executive function, working memory, processing speed, and motor deficits). PWH had higher odds of Dysexecutive/Slow membership, which related to CVD risk and higher vascular dysfunction, but not inflammation, in PWH. Vascular biomarkers moderated adverse HIV effects on executive function, processing speed, and working memory such that PWH had lower T-scores only when vascular dysfunction was high.ConclusionsIn PWH with controlled disease, peripheral markers of endothelial dysfunction and vascular permeability are selectively associated with an empirically-derived subgroup that exhibits domain deficits commonly impacted by cerebrovascular disease. Findings support the presence of a vascular NCI subgroup of PWH who may benefit from interventions that directly target the neurovascular unit.

Objective: Poor sleep quality is related to worse neurocognition in older adults and in people with HIV (PWH); however, many previous studies have relied only on self-report sleep questionnaires, which are inconsistently correlated with objective sleep measures. We examined relationships between objective and subjective sleep quality and neurocognition in persons with and without HIV, aged 50 and older. Method: Eighty-five adults (PWH n = 52, HIV-negative n = 32) completed comprehensive neuropsychological testing to assess global and domain-specific neurocognition. Objective sleep quality was assessed with wrist actigraphy (total sleep time, efficiency, sleep fragmentation) for five to 14 nights. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index. Results: Objective and subjective sleep measures were unrelated (p's > 0.30). Compared to HIV-negative participants, PWH had greater sleep efficiency (80% vs. 75%, p = 0.05) and were more likely to be using prescription and/or over the counter sleep medication (p = 0.04). In the whole sample, better sleep efficiency (p

BackgroundTo investigate joint contributions of cognitive and physiologic reserve to neurocognitive SuperAging in older persons with HIV (PWH).MethodsParticipants included 396 older PWH (age range: 50-69 years) who completed cross-sectional neuropsychological and neuromedical evaluations. Using published criteria, participants exhibiting global neurocognition within normative expectations of healthy 25-year-olds were classified as SuperAgers (SA; n = 57). Cognitively normal (CN; n = 172) and impaired (n = 167) participants were classified with chronological age-based norms. Cognitive reserve was operationalized with an estimate of premorbid verbal intelligence, and physiologic reserve was operationalized with a cumulative index of 39 general and HIV-specific health variables. Analysis of variance with confirmatory multinomial logistic regression examined linear and quadratic effects of cognitive and physiologic reserve on SA status, adjusting for chronological age, depression, and race/ethnicity.ResultsUnivariably, SA exhibited significantly higher cognitive and physiologic reserve compared with CN and cognitively impaired ( d s ≥ 0.38, p s < 0.05). Both reserve factors independently predicted SA status in multinomial logistic regression; higher physiologic reserve predicted linear increases in odds of SA, and higher cognitive reserve predicted a quadratic "J-shaped" change in odds of SA compared with CN (ie, odds of SA > CN only above 35th percentile of cognitive reserve).ConclusionsEach reserve factor uniquely related to SA status, which supports the construct validity of our SA criteria and suggests cognitive and physiologic reserve reflect nonoverlapping pathways of neuroprotection in HIV. Incorporation of proxy markers of reserve in clinical practice may improve characterization of age-related cognitive risk and resilience among older PWH, even among PWH without overt neurocognitive impairment.

ObjectiveTo assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease.MethodsParticipants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments.ResultsFifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants' scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients.InterpretationEarly in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/µl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance.

We evaluated whether biomarkers of age-related neuronal injury and amyloid metabolism are associated with neurocognitive impairment (NCI) in people with and without HIV (PWH, PWoH). This was a cross-sectional study of virally suppressed PWH and PWoH. NCI was assessed using a validated test battery; global deficit scores (GDS) quantified overall performance. Biomarkers in cerebrospinal fluid (CSF) were quantified by immunoassay: neurofilament light (NFL), total Tau (tTau), phosphorylated Tau 181 (pTau181), amyloid beta (Aβ)42, and Aβ40. Factor analysis was used to reduce biomarker dimensionality. Participants were 256 virally suppressed PWH and 42 PWoH, 20.2% female, 17.1% Black, 7.1% Hispanic, 60.2% non-Hispanic White, and 15.6% other race/ethnicities, mean (SD) age 56.7 (6.45) years. Among PWH, the best regression model for CSF showed that higher tTau (β = 0.723, p = 3.79e-5) together with lower pTau181 (β = -0.510, p = 0.0236) best-predicted poor neurocognitive performance. In univariable analysis, only higher tTau was significantly correlated with poor neurocognitive performance (tTau r = 0.214, p = 0.0006; pTau181 r = 0.00248, p = 0.969). Among PWoH, no CSF biomarkers were significantly associated with worse NCI. Predicted residual error sum of squares (PRESS) analysis showed no evidence of overfitting. Poorer neurocognitive performance in aging PWH was associated with higher CSF tTau, a marker of age-related neuronal injury, but not with biomarkers of amyloid metabolism. The findings suggest that HIV might interact with age-related neurodegeneration to contribute to cognitive decline in PWH.

Despite the neurocognitive risks of aging with HIV, initial cross-sectional data suggest a subpopulation of older people with HIV (PWH) possess youthful neurocognition (NC) characteristic of SuperAgers (SA). Here we characterize longitudinal NC trajectories of older PWH and their convergent validity with baseline SA status, per established SuperAging criteria in PWH, and baseline biopsychosocial factors. Growth mixture modeling (GMM) identified longitudinal NC classes in 184 older (age ≥ 50-years) PWH with 1-5 years of follow-up. Classes were defined using 'peak-age' global T-scores, which compare performance to a normative sample of 25-year-olds. 3-classes were identified: Class 1Stable Elite (n = 31 [16.8%], high baseline peak-age T-scores with flat trajectory); Class 2Quadratic Average (n = 100 [54.3%], intermediate baseline peak-age T-scores with u-shaped trajectory); Class 3Quadratic Low (n = 53 [28.8%], low baseline peak-age T-scores with u-shaped trajectory). Baseline predictors of Class 1Stable Elite included SA status, younger age, higher cognitive and physiologic reserve, and fewer subjective cognitive difficulties. This GMM analysis supports the construct validity of SuperAging in older PWH through identification of a subgroup with longitudinally-stable, youthful neurocognition and robust biopsychosocial health.

BackgroundWe hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S).MethodsA total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and β2 microglobulin (β2m) in the CSF and serum were quantified using different immunoassays.ResultsOverall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum β2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and β2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum β2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024).DiscussionWe observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

BackgroundTo examine longitudinal neurocognitive decline among Latino, non-Latino Black, and non-Latino White people with HIV (PWH) and factors that may explain ethnic/racial disparities in neurocognitive decline.MethodsFour hundred ninety nine PWH (13.8% Latino, 42.7% Black, 43.5% White; baseline age: M = 43.5) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed neurocognitive, neuromedical, and laboratory assessments every 6-12 months with up to 5 years of follow-up. Longitudinal neurocognitive change was determined via published regression-based norms. Survival analyses investigated the relationship between ethnicity/race and neurocognitive change, and baseline and time-dependent variables that may explain ethnic/racial disparities in neurocognitive decline, including socio-demographic, HIV-disease, medical, psychiatric, and substance use characteristics.ResultsIn Cox proportional hazard models, hazard ratios for neurocognitive decline were increased for Latino compared with White PWH (HR = 2.25, 95% CI = 1.35 to 3.73, P = 0.002), and Latino compared with Black PWH (HR = 1.86, 95% CI = 1.14 to 3.04, P = 0.013), with no significant differences between Black and White PWH (P = 0.40). Comorbidities, including cardiometabolic factors and more severe neurocognitive comorbidity classification, accounted for 33.6% of the excess hazard for Latino compared with White PWH, decreasing the hazard ratio associated with Latino ethnicity (HR = 1.83, 95% CI = 1.06 to 3.16, P = 0.03), but did not fully account for elevated risk of decline.ConclusionsLatino PWH may be at higher risk of early neurocognitive decline compared with Black and White PWH. Comorbidities accounted for some, but not all, of this increased risk among Latino PWH. Future research examining institutional, sociocultural, and biomedical factors, including structural discrimination and age-related biomarkers, may further explain the observed disparities.

Monocytes and macrophages activation are crucial in human immunodeficiency virus (HIV) central nervous system (CNS) infection and HIV associated neurocognitive disorders (HAND) pathogenesis. The soluble form of CD14 (sCD14) is a marker of monocyte activation. We hypothesized that sCD14 levels would be lower in people with HIV-1 subtype C (HIV-1C) than in HIV-1B owing to a variant Tat cysteine dimotif (C30S31) with reduced chemotactic activity. A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH); 27 samples of the HIV-1B subtype and 40 of the non-B HIV-1 subtypes (including 26,HIV-1C), and 18 HIV-negative controls were included. sCD14 levels were quantified using a high-sensitivity enzyme-linked immunosorbent assay. sCD14 increase in serum, but not in CSF, was higher in samples from HIV-1B than HIV-1C (p = 0.002; Cohen's d, 0.7). CSF or serum sCD14 values were not correlated with global deficit score or specific cognitive domains. The impact of HIV-1 on monocyte stimulation biomarkers evaluated by sCD14 in serum was subtype-dependent, higher in HIV-1B than HIV-1C, consistent with reduced chemotactic activity as hypothesized.

ObjectiveThe aim of this study was to determine whether there are relationships between fatigue, cognition, and everyday functioning in older persons with and without HIV and to examine if associations remain after accounting for depression, anxiety, and sleep quality.MethodsSixty-nine persons with HIV (PWH) and 36 persons without HIV, aged 50-74 years, were recruited from ongoing studies at UC San Diego's HIV Neurobehavioral Research Program and from the community. Participants completed neuropsychological testing, a performance-based measure of everyday functioning, and self-report questionnaires of fatigue, depression, anxiety, sleep quality, and everyday functioning. Multivariable linear regressions and logistic regressions stratified by HIV serostatus were used to examine relationships between fatigue, cognition, and everyday functioning. Psychiatric symptoms and sleep quality were examined as covariates.ResultsIn this cross-sectional study, PWH had significantly greater fatigue than the HIV-negative group (g  = 0.83; P

BackgroundAge-related comorbidities accumulate faster in people with HIV (PWH) than in those without HIV. We evaluated whether a validated multimorbidity scale, the Charlson index, predicted neurocognitive trajectories in PWH.MethodsScaled scores of a comprehensive neuropsychological battery were averaged across all visits. Multilevel modeling examined between- and within-person predictors of global neurocognition. At the between-person level, averaged Charlson scores were examined as a predictor of neurocognitive change rate, covarying for HIV disease characteristics. Within-persons, visit-specific Charlson index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for disease measures.ResultsParticipants were 1195 PWH (mean baseline age: 43.0; SD: 9.7 years) followed for a mean of 7.1 years (range: 0.5-20.5). At the between-person level, more rapid neurocognitive worsening correlated with higher (worse) average Charlson scores (standardized β: -0.062; SE: 0.015; P = .001) and lower CD4 nadir (standardized β: 0.055; SE: 0.021; P = .011), but not viral suppression or average CD4+ lymphocytes (P > .05). At the within-person level, poorer visit-specific neurocognition was related to worse concurrent, but not preceding, Charlson scores (standardized β: -0.046; SE: 0.015; P = .003), detectable HIV viral load (standardized β: 0.018; SE: 0.006; P = .001), and higher CD4+ (standardized β: 0.043; SE: 0.009; P < .001).ConclusionsThe impact of comorbidities on neurocognitive decline exceeded that of HIV disease factors. Although correlative, the temporal relationships suggested that treatment of comorbidities might improve neurocognitive prognosis for PWH.

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-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.

HIV-associated neurocognitive disorders (HAND) remain highly prevalent in people with HIV (PWH). Studies suggested that certain sociodemographic factors are associated with the risk of HAND in PWH. Here we investigated the impact of HIV infection and demographics on functional brain networks. One run of 8.5 min resting state functional MRI (fMRI) data was collected from 101 PWH (41-70 years old) and 40 demographically comparable controls. Functional connectivity (FC) was calculated using average wavelet coherence. The impact of demographic factors on FCs was investigated using canonical correlation analysis (CCA). Wavelet coherence analysis revealed a reduced within-network connectivity in the dorsal somatomotor network (dSMN), along with a reduced between-network connectivity between dSMN and medial temporal lobe (MTL) in PWH (compared to controls). Across all participants, CCA revealed that older age and HIV infection had negative impacts on network connectivity measures (mainly reduced within- and between-network FCs), whereas education had an opposite effect. In addition, being female at birth or a member of a minority ethnic/racial group was also associated with network disruptions. Our data suggested that advanced age and HIV infection are risk factors for functional brain network disruptions, whereas higher educational attainment was linked to better preserved functional network connectivity.

In spite of suppressive antiretroviral therapies (ART), Human Immunodeficiency Virus (HIV)-infected subjects still experience the consequences of viral persistence and chronic inflammation. In the brain, where most HIV-1 targets are of innate immune origin, neurological and cognitive impairments are detectable and enhanced by highly prevalent substance use disorders. Cannabis is one of the most prevalent substances among HIV+ ​subjects, compared to non-infected populations, either prescribed for improving various symptoms or used recreationally, as well as a component of polysubstance use. The mechanisms by which addictive substances and HIV interact are multifactorial and poorly understood. Importantly, the HIV brain target cells, macrophages and microglia, express receptors to neurotransmitters elevated by such drugs, and express receptors to cannabinoids, particularly CB2R. We have tested a panel of 784 transcripts associated with neurological disorders, digitally multiplexed and detectable in peripheral blood cells from a small cohort (n ​= ​102) of HIV-positive (HIV+) and HIV-negative (HIV-) specimens, stratified based on criteria of lifetime (LT) dependence of cannabis (CAN+) or not (CAN-). Demographic homogeneity and low incidence of co-morbidities helped increase power and allowed the identification of key differences consistent with HIV infection, cannabis exposure, or their interactions. A small percentage of these subjects used cannabis as well as other drugs. The data was analyzed using robust systems and visualization strategies to detect orchestrated patterns in gene networks connected based on molecular interfaces with higher power than in single genes. We found that the effects of cannabis differed drastically between HIV- and HIV+ ​groups, particularly in gene networks playing a role in inflammation, neurodegeneration, apoptosis and leukocyte adhesion and transmigration. At the level of individual genes, we identified detrimental effects that were associated with polysubstance use as a covariate, particularly methamphetamine. Transcription factor usage predictions suggest that the effects of cannabis are associated with transcriptional co-regulation at the gene promoters by multiple factors that vary by context. Overall, we have found that the effects of cannabis may be context-dependent, with potential benefits in the context of HIV reflected by improvements in cognition, but in the absence of the polysubstance use component.

Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH). We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns. Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men, 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822), respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's phylogenetic diversity in PWH (Spearman's ρ = .224, P = 0.0007), but not in PWoH (Spearman's ρ = .032, P = .748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, P = 1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, P = 6.24e-5). Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP. PERSPECTIVE: The association of neuropathic pain in people with HIV with reduced gut microbial diversity and dysbiosis raises the possibility that re-establishing a healthy gut microbiota might ameliorate neuropathic pain in HIV by reducing proinflammatory and increasing anti-inflammatory microbial products.

Given the co-occurrence of memory impairment in HIV-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment/Alzheimer's disease (aMCI/AD), biomarkers are needed that can disentangle these conditions among people with HIV (PWH). We assessed whether cerebrospinal fluid (CSF) markers of AD could help in this effort by determining their relationship to learning and memory deficits versus cognitive deficits more characteristic of HAND than aMCI/AD (processing speed and complex visual/motor coordination) among 31 older PWH. CSF amyloid-β42 phosphorylated-tau, amyloid-β40/amyloid-β42 and phosphorylated-tau/amyloid-β42 ratio related to learning/memory performance but not HAND-related deficits, suggesting that these biomarkers may have utility in disentangling aMCI/AD from HAND.

Older people with HIV (PWH) experience heightened risk for the acquisition of cumulative, multisystem decline, that is, frailty syndrome. Frailty relates to poorer sleep quality in the general older adult population; however, this association has yet to be explored among PWH. A cross-sectional analysis of 285 PWH ≥50 years of age (mean age 60.5 ± 7.0) examined the relationship between frailty (Fried frailty phenotype) and self-reported sleep quality [Pittsburgh Sleep Quality Index (PSQI)]. Three separate multivariable linear regression models examined global PSQI as a function of (1) frailty phenotype, (2) total number of frailty symptoms, or (3) specific individual frailty symptoms. Models covaried for demographic and biopsychosocial risk factors, including age, sex, race/ethnicity, education, premorbid verbal IQ estimate, current depressive symptoms, and diagnosis of a substance abuse disorder. Compared to nonfrail (B = 0.151; p = .021) and prefrail (B = 0.144; p = .021), frail phenotype was related to poorer sleep quality (increased global PSQI; F(5,278) = 11.34, p

BackgroundAstrocytes become activated with certain infections, and this might alter the brain to trigger or worsen depressed mood. Indeed, astrocytes are chronically activated in people with HIV infection (PWH), who are much more frequently depressed than people without HIV (PWoH). A particularly disabling component of depression in PWH is apathy, a loss of interest, motivation, emotion, and goal-directed behavior. We tested the hypothesis that depression and apathy in PWH would be associated with higher levels of a biomarker of astrocyte activation, glial fibrillary acidic protein (GFAP), in cerebrospinal fluid (CSF).MethodsWe evaluated PWH in a prospective observational study using the Beck Depression Inventory-II (BDI-II) and additional standardized assessments, including lumbar puncture. We measured GFAP in CSF with a customized direct sandwich ELISA method. Data were analyzed using ANOVA and multivariable regression.ResultsParticipants were 212 PWH, mean (SD) age 40.9±9.14 years, median (IQR) nadir and current CD4 199 (57, 326) and 411 (259, 579), 65.1% on ART, 67.3% virally suppressed. Higher CSF GFAP correlated with worse total BDI-II total scores (Pearson correlation r=0.158, p-value=0.0211), and with worse apathy scores (r=0.205, p=0.0027). The correlation between apathy/depression and GFAP was not in fluenced by other factors such as age or HIV suppression status.ConclusionsAstrocyte activation, reflected in higher levels of CSF GFAP, was associated with worse depression and apathy in PWH. Interventions to reduce astrocyte activation -- for example, using a peptide-1 receptor (GLP-1R) agonist -- might be studied to evaluate their impact on disabling depression in PWH.

HIV-associated distal neuropathic pain (DNP) is one of the most prevalent, disabling, and treatment-resistant complications of HIV, but its biological underpinnings are incompletely understood. While data specific to mechanisms underlying HIV DNP are scarce, functional neuroimaging of chronic pain more broadly implicates the role of altered resting-state functional connectivity within and between salience network (SN) and default mode network (DMN) regions. However, it remains unclear the extent to which HIV DNP is associated with similar alterations in connectivity. The current study aimed to bridge this gap in the literature through examination of resting-state functional connectivity patterns within SN and DMN regions among people with HIV (PWH) with and without DNP. Resting state functional magnetic resonance imaging (rs-fMRI) scans were completed among 62 PWH with HIV-associated peripheral neuropathy, of whom 27 reported current DNP and 35 did not. Using subgrouping group iterative multiple estimation, we compared connectivity patterns in those with current DNP to those without. We observed weaker connectivity between the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) and stronger connectivity between the anterior cingulate cortex (ACC) and thalamus among those reporting DNP. Overall, these findings implicate altered within DMN (i.e., MPFC-PCC) and within SN (i.e., ACC-thalamus) connectivity as potential manifestations of adaptation to pain from neuropathy and/or mechanisms underlying the development/maintenance of DNP. Findings are discussed in the context of differential brain response to pain (i.e., mind wandering, pain aversion, pain facilitation/inhibition) and therapeutic implications.

BackgroundNeuronal dysfunction plays an important role in the high prevalence of HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH). Transcranial direct current stimulation (tDCS)-with its capability to improve neuronal function-may have the potential to serve as an alternative therapeutic approach for HAND. Brain imaging and neurobehavioral studies provide converging evidence that injury to the anterior cingulate cortex (ACC) is highly prevalent and contributes to HAND in PWH, suggesting that ACC may serve as a potential neuromodulation target for HAND. Here we conducted a randomized, double-blind, placebo-controlled, partial crossover pilot study to test the safety, tolerability, and potential efficacy of anodal tDCS over cingulate cortex in adults with HIV, with a focus on the dorsal ACC (dACC).MethodsEleven PWH (47-69 years old, 2 females, 100% African Americans, disease duration 16-36 years) participated in the study, which had two phases, Phase 1 and Phase 2. During Phase 1, participants were randomized to receive ten sessions of sham (n = 4) or cingulate tDCS (n = 7) over the course of 2-3 weeks. Treatment assignments were unknown to the participants and the technicians. Neuropsychology and MRI data were collected from four additional study visits to assess treatment effects, including one baseline visit (BL, prior to treatment) and three follow-up visits (FU1, FU2, and FU3, approximately 1 week, 3 weeks, and 3 months after treatment, respectively). Treatment assignment was unblinded after FU3. Participants in the sham group repeated the study with open-label cingulate tDCS during Phase 2. Statistical analysis was limited to data from Phase 1.ResultsCompared to sham tDCS, cingulate tDCS led to a decrease in Perseverative Errors in Wisconsin Card Sorting Test (WCST), but not Non-Perseverative Errors, as well as a decrease in the ratio score of Trail Making Test-Part B (TMT-B) to TMT-Part A (TMT-A). Seed-to-voxel analysis with resting state functional MRI data revealed an increase in functional connectivity between the bilateral dACC and a cluster in the right dorsal striatum after cingulate tDCS. There were no differences in self-reported discomfort ratings between sham and cingulate tDCS.ConclusionsCingulate tDCS is safe and well-tolerated in PWH, and may have the potential to improve cognitive performance and brain function. A future study with a larger sample is warranted.

Chronic pain affects ~10-20% of the U.S. population with an estimated annual cost of $600 billion, the most significant economic cost of any disease to-date. Neuropathic pain is a type of chronic pain that is particularly difficult to manage and leads to significant disability and poor quality of life. Pain biomarkers offer the possibility to develop objective pain-related indicators that may help diagnose, treat, and improve the understanding of neuropathic pain pathophysiology. We review neuropathic pain mechanisms related to opiates, inflammation, and endocannabinoids with the objective of identifying composite biomarkers of neuropathic pain. In the literature, pain biomarkers typically are divided into physiological non-imaging pain biomarkers and brain imaging pain biomarkers. We review both types of biomarker types with the goal of identifying composite pain biomarkers that may improve recognition and treatment of neuropathic pain.

BackgroundThe association between long-term cannabis use and balance disturbances has not been investigated in people living with HIV (PWH). We hypothesized that long-term cannabis use in PWH might be associated with more deleterious effects on balance than in HIV seronegative individuals due to potential neurotoxic interactions between HIV and cannabis.MethodsThree thousand six-hundred and forty-eight participants with and without HIV completed an interviewer-administered timeline follow-back assessment to assess lifetime days and quantity of cannabis use and other cannabis use characteristics. A structured clinical interview was used to collect any history of balance disturbance. Comparisons between HIV+ vs the HIV- groups and moderate-severe vs. no or minimal imbalance in participant characteristics (demographics, cannabis use, medication currently used, and neurological disease) were performed using Student t tests for continuous variables and Fisher's exact test for binary and categorical variables. Multivariate logistic regression was applied to determine the interaction effect of total quantity of cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen's d or odds ratios.ResultsOn average, participants were 45.4 years old (SD = 11 years), primarily male (77.7%), and non-Hispanic white (48.1%). A majority of participants were HIV+ (79.1%). Four hundred thirty (11.9%) of the participants reported balance disturbances within the past 10 years. PWH were more likely to have balance disturbances than demographically matched HIV-uninfected participants (odds ratio [OR] 2.66, 95% CI 1.91-3.7). Participants with moderate-severe balance disturbances did not differ from those with no or minimal imbalance in the proportion who had ever used cannabis (73.8% vs. 74.4%; p = 0.8) (OR 1.03, 95% CI 0.80-1.32) neither did they have a higher total amount of cannabis use (4871 vs. 4648; p = 0.3) (Cohen's d 0.11, 95% CI 0.01-0.14). In the HIV- population, those with balance disturbances reported more total amount of cannabis use as compared to those with normal balance (11316 vs 4154; p = 0.007). In the HIV+ population on the other hand, there was no significant association (4379 vs 4773; p = 0.6).ConclusionsWe found unexpectedly that while long-term cannabis use in HIV- individuals was associated with more severe balance disturbances, there were no associations in HIV+ individuals. This suggests that cannabis use in HIV is safe with respect to balance disturbances. Given that HIV is related to persistent inflammation despite virologic suppression on antiretroviral therapy, future mechanistic studies are needed to determine whether HIV-associated inflammation contributes to the higher prevalence of balance disturbance in HIV+ individuals and whether cannabinoids have anti-inflammatory effects that mitigate HIV-associated balance disturbance.

The number of people with HIV (PWH) aged 50 years or older continues to steadily increase. The convergence of age- and HIV-related complications in these individuals presents a challenge for both patients and clinicians alike. New findings continue to emerge, as numerous researchers evaluate the combined impact of these two factors on quality of life, physiological systems, and mental health in PWH. Since its first occurrence in 2009, the International Workshop on HIV and Aging has served as a multidisciplinary meeting to share basic biomedical data, clinical trial results, treatment strategies, and epidemiological recommendations, toward better understanding and outcomes among like-minded scientific professionals. In this article, we share a selection of key findings presented in plenary talks at the 11th Annual International Workshop on HIV and Aging, held virtually from September 30, 2020 to October 2, 2020. We will also address the future directions of HIV and aging research, to further assess how the aging process intersects with chronic HIV.