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Prevalence and incidence of HIV among people aged 50 years and older continue to rise worldwide, generating increasing awareness among care providers, scientists, and the HIV community about the importance of brain health in older adults with HIV. Many age-related factors that adversely affect brain health can occur earlier and more often among people with HIV, including epigenetic ageing, chronic medical conditions (eg, cardiovascular disease), and age-related syndromes (eg, frailty). Extensive dialogue between HIV community leaders, health-care providers, and scientists has led to the development of a multidimensional response strategy to protect and enhance brain health in people ageing with HIV that spans across public health, clinical spaces, and research spaces. This response strategy was informed by integrated ageing care frameworks and is centred on prevention, early detection, and management of brain health issues associated with HIV (eg, neurocognitive disorders), with specific considerations for low-resource or middle-resource countries. A collaborative, international, and data-informed update of the diagnostic criteria for HIV-associated neurocognitive disorders is a cornerstone of the proposed response strategy. The proposed response strategy includes a dynamic, international, online knowledge hub that will provide a crucial community resource for emerging evidence on the brain health of people ageing with HIV., Competing Interests: Declaration of interests BJB reports royalties from Oxford University Press and Cambridge University Press; honoraria for presentations sponsored by the Neurological Association of South Africa, Jansen, and Biogen; patents (monoclonal antibody for quinolinic acid as part of test kit for monitoring multiple sclerosis severity and progression [PCT/IB2013/055902; patent office Australia], 2010; method and prognostic kit for monitoring multiple sclerosis [WO/2015/008111], 2013; and automatic fall and seizure detector [application number 2016904045 IP Australia Batch Reference SPBI-0001069085 by My Medic Watch]); a position as Chairperson of the data monitoring and ethics committee for the Lighthouse 2 phase 3 study of the antiretroviral Triumeq in Amyotrophic Lateral Sclerosis (King's College London, UK, and Tysabri Advisory Board Australia); and a role as a past President of the International Society for Neurovirology (2019–23). JV reports honoraria for presentations and research grants in trials sponsored by Merck, Janssen Cilag, ViiV Healthcare, and Gilead Sciences. KG reports support from the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACGT) Network (funded by the US National Institutes of Health) as Protocol Director for ACTG trial A5402, Cipla, and Dr Reddy's Laboratories. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Identifying persons with HIV (PWH) at increased risk for Alzheimer's disease (AD) is complicated because memory deficits are common in HIV-associated neurocognitive disorders (HAND) and a defining feature of amnestic mild cognitive impairment (aMCI; a precursor to AD). Recognition memory deficits may be useful in differentiating these etiologies. Therefore, neuroimaging correlates of different memory deficits (i.e., recall, recognition) and their longitudinal trajectories in PWH were examined., Design: We examined 92 PWH from the CHARTER Program, ages 45-68, without severe comorbid conditions, who received baseline structural MRI and baseline and longitudinal neuropsychological testing. Linear and logistic regression examined neuroanatomical correlates (i.e., cortical thickness and volumes of regions associated with HAND and/or AD) of memory performance at baseline and multilevel modeling examined neuroanatomical correlates of memory decline (average follow-up = 6.5 years)., Results: At baseline, thinner pars opercularis cortex was associated with impaired recognition ( p = 0.012; p = 0.060 after correcting for multiple comparisons). Worse delayed recall was associated with thinner pars opercularis ( p = 0.001) and thinner rostral middle frontal cortex ( p = 0.006) cross sectionally even after correcting for multiple comparisons. Delayed recall and recognition were not associated with medial temporal lobe (MTL), basal ganglia, or other prefrontal structures. Recognition impairment was variable over time, and there was little decline in delayed recall. Baseline MTL and prefrontal structures were not associated with delayed recall., Conclusions: Episodic memory was associated with prefrontal structures, and MTL and prefrontal structures did not predict memory decline. There was relative stability in memory over time. Findings suggest that episodic memory is more related to frontal structures, rather than encroaching AD pathology, in middle-aged PWH. Additional research should clarify if recognition is useful clinically to differentiate aMCI and HAND.

N -acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N -acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N -acyl lipid patterns from 2,700 public datasets, identifying 851 N -acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N -acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery., Competing Interests: Declaration of interests: PCD: PCD is an advisor and holds equity in Cybele, BileOmix and Sirenas and a Scientific co-founder, advisor and holds equity to Ometa, Enveda, and Arome with prior approval by UC-San Diego. PCD also consulted for DSM animal health in 2023. MW: MW is a co-founder of Ometa Labs LLC. RK: Rob Knight is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

Despite extensive efforts, extracting information on medication exposure from clinical records remains challenging. To complement this approach, we developed the tandem mass spectrometry (MS/MS) based GNPS Drug Library. This resource integrates MS/MS data for drugs and their metabolites/analogs with controlled vocabularies on exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data independent of clinical records. Our library facilitates stratification of individuals in clinical studies based on the empirically detected medications, exemplified by drug-dependent microbiota-derived N -acyl lipid changes in a cohort with human immunodeficiency virus. The GNPS Drug Library holds potential for broader applications in drug discovery and precision medicine.

Objective: Risk factors for progression from prediabetes mellitus (pre-DM) to diabetes mellitus (DM) among people with HIV (PWH) receiving modern antiretroviral therapy (ART) require better characterization., Design: AIDS Clinical Trials Group (ACTG) A5322 (HAILO) was an observational cohort study of PWH ≥40 years old. Participants initiated ART through ACTG randomized clinical trials., Methods: We used Cox proportional hazards regression models to identify risk factors for development of DM among HAILO participants with pre-DM., Results: Among 1035 HAILO participants, 74 (7%) had pre-DM at entry and another 679 (66%) developed pre-DM during follow-up. Of 753 PWH with pre-DM, 167 (22%) developed DM. In multivariable models, the risk of developing DM was greater with higher BMI, lower CD4 count (≤200 cells/mm 3 ), hypertriglyceridemia, or higher waist circumference at pre-DM diagnosis ( P  < 0.01)., Conclusion: Rates of pre-DM and progression to DM remain high among virally suppressed PWH receiving modern ART regimens. Traditional risks for DM, such as higher BMI or waist circumference, are associated with increased risk of incident DM among PWH with pre-DM. The association between lower CD4 + and progression to DM suggests a role for advanced immunodeficiency and inflammation. Further investigation of interventions aimed at preventing DM among PWH with pre-DM is needed. Optimizing prevention and treatment for DM may be an intervenable opportunity to improve long-term outcomes for PWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

People with HIV and comorbid substance use problems may be among those who benefit most from long-acting HIV antiretroviral treatment, but they are routinely excluded from Phase 3 clinical trials. Their inclusion would permit an examination of the clinical value of long-acting therapies for people with adherence problems and an exploration of syndemic interactions between HIV, mental health conditions, and substance use problems, which compound into a major challenge in the efforts to end the HIV epidemic., Competing Interests: Competing interest’s statement The authors declare no conflicts of interest.

Background: Older people with human immunodeficiency virus (HIV, PWH) are prone to using multiple medications due to higher rates of medical comorbidities and the use of antiretroviral therapy (ART). We assessed the prevalence and clinical impact of polypharmacy among PWH., Methods: We leveraged clinical data from the AIDS Clinical Trials Group A5322 study "Long-Term Follow-up of Older HIV-infected Adults: Addressing Issues of Aging, HIV Infection and Inflammation" (HAILO). We included PWH aged ≥40 years with plasma HIV RNA levels <200 copies/µL. We assessed the relationship between polypharmacy (defined as the use of 5 or more prescription medications, excluding ART) and hyperpolypharmacy (defined as the use of 10 or more prescription medications, excluding ART) with slow gait speed (less than 1 meter/second) and falls, including recurrent falls., Results: Excluding ART, 24% of study participants had polypharmacy and 4% had hyperpolypharmacy. Polypharmacy was more common in women (30%) than men (23%). Participants with polypharmacy had a higher risk of slow gait speed (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.27-2.50) and increased risk of recurrent falls (OR = 2.12; 95% CI = 1.06-4.23). The risk for recurrent falls was further increased in those with hyperpolypharmacy compared with those without polypharmacy (OR = 3.46; 95% CI = 1.32-9.12)., Conclusions: In this large, mixed-sex cohort of PWH aged ≥40 years, polypharmacy was associated with slow gait speed and recurrent falls, even after accounting for medical comorbidities, alcohol use, substance use, and other factors. These results highlight the need for increased focus on identifying and managing polypharmacy and hyperpolypharmacy in PWH., Competing Interests: Potential conflicts of interest. K. M. E. reports grants or contracts from Gilead and ViiV paid to their institution; consulting fees from Merck and Gilead; support for attending meetings and/or travel from ViiV paid to their institution; and holding a leadership or fiduciary role for the AIDS Clinical Trials Group paid to the NIH. S. L. reports grants or contracts from the NIH and Merck and support for attending meetings and/or travel from Virology Education. Q. M. reports consulting fees from Change Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Mitochondrial DNA (mtDNA) genetic variation is associated with neurocognitive (NC) impairment (NCI) in people with HIV (PWH). Other approaches use sequence conservation and protein structure to predict the impact of mtDNA variants on protein function. We examined predicted mtDNA variant pathogenicity in the CHARTER study using MutPred scores, hypothesizing that persons with higher scores (greater predicted pathogenicity) have more NCI., Methods: CHARTER included NC testing in PWH from 2003 to 2007. MutPred scores were assigned to CHARTER participants with mtDNA sequence; any score > 0.5 was considered potentially deleterious. Outcomes at cohort entry were NCI, defined by global and seven NC domain deficit scores, and by mean global and domain NC performance T-scores. Univariate and multivariable regression analyses assessed associations between having a deleterious variant and NCI. Additional models included estimated peripheral blood cell mtDNA copy number., Results: Data were available for 744 PWH (357 African ancestry; 317 European; 70 Hispanic). In the overall cohort, PWH having any potentially deleterious variant were less likely to have motor impairment (16 vs. 25 %, p = 0.001). In multivariable analysis, having a deleterious variant remained associated with lower likelihood of motor impairment (adjusted odds ratio 0.59 [95 % CI 0.41-0.88]; p = 0.009), and better motor performance by T-score (β 1.71 [0.31-3.10], p = 0.02). Associations persisted after adjustment for estimated mtDNA quantity., Conclusions: In these PWH, having a potentially deleterious mtDNA variant was associated with less motor impairment. These unexpected findings suggest that potentially deleterious mtDNA variations may confer protection against impaired motor function by as yet unknown mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

We examined whether cognitive reserve moderated the relationship between neurodegeneration and cognition in 67 postmortem persons with HIV (PWH) who were cognitively assessed within 1 year of death. Cognitive reserve was measured via the Wide Range Achievement Test-4 reading subtest (WRAT4). Synaptodendritic neurodegeneration was based on densities of synaptophysin and microtubule-associated protein 2 immunohistochemical reactivity in frontal cortex, and categorized as minimal, moderate, or severe (tertile-split). T-Scores from 15 cognitive tests were averaged into a global cognitive T-score. Among those with low cognitive reserve (based on WRAT4 median split), the moderate neurodegeneration group showed cognition that was poorer than the minimal neurodegeneration group and comparable to the severe neurodegeneration group. Among those with high cognitive reserve, the moderate neurodegeneration group showed cognition comparable to the minimal neurodegeneration group and better than the severe neurodegeneration group. High cognitive reserve may buffer against cognitive impairment among PWH with moderate, but not severe, neurodegeneration., (© 2023. The Author(s) under exclusive licence to The Journal of NeuroVirology, Inc.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8 +  and CD4 +  T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Persons 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., Methods: Six 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., Results: Participants 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., Interpretation: We 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., Competing Interests: None., (© 2023 The Authors. Published by Elsevier Inc.)

Older persons with HIV (PWH) experience high rates of cognitive impairment and frailty, and accelerated decline in physical function compared with the general population. Metformin use has been associated with beneficial effects on cognitive and physical function among older adults without HIV. The relationship between metformin use on these outcomes in PWH has not been evaluated. AIDS Clinical Trials Group (ACTG) A5322 is an observational cohort study of older PWH with annual assessments for cognition and frailty, including measures of physical function (e.g., gait speed and grip strength). Participants with diabetes who were prescribed antihyperglycemic medications were included in this analysis to evaluate the association between metformin and functional outcomes. Cross-sectional, longitudinal, and time-to-event models were used to evaluate the relationship between metformin exposure with cognitive, physical function, and frailty outcomes. Ninety-eight PWH met inclusion criteria and were included in at least one model. No significant associations between metformin use, frailty, physical, or cognitive function were noted in unadjusted or adjusted cross-sectional, longitudinal, or time-to-event models ( p  > .1 for all models). This study is the first to examine the association between metformin use on functional outcomes among older PWH. Although it did not ascertain significant associations between metformin use and functional outcomes, our small sample size, restriction to persons with diabetes, and lack of randomization to metformin therapy were limitations. Larger randomized studies are needed to determine whether metformin use has beneficial effects on cognitive or physical function in PWH. Clinical Trial Registration numbers: 02570672, 04221750, 00620191, and 03733132.

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.

Introduction: An 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., Methods: This 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)., Results: Thirty-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., Conclusion: During 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ene, Duiculescu, Radoi, Lazar, Tardei, Ungureanu, Ruta, Vinters, Letendre, Grant, Ellis and Achim.)

Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive impairment in people living with HIV. Data suggest that cardiovascular risk may play a greater role in cognitive health in women than in men with HIV., Methods: We performed a cross-sectional study of 104 participants with virologically suppressed HIV from 2 clinics in urban China. Participants underwent neuropsychological testing from which we calculated T scores globally and in 5 cognitive domains. We assessed cerebral vasoreactivity of the middle cerebral arteries in response to breath holding. We constructed linear regression models to determine associations between cerebrovascular and cognitive function overall and stratified by sex., Results: Women were younger than men (48 versus 51 years, P = 0.053), had fewer years of education (9 years versus 12 years, P = 0.004), and fewer cardiometabolic risk factors (0 versus 1 factor, P = 0.008). In a model with all participants, cerebrovascular function was significantly associated with global cognition (2.74 higher T score per 1-point higher cerebral vasoreactivity [SE 1.30], P = 0.037). Cerebrovascular function remained significantly associated with global cognition among women (4.15 higher T score [SE 1.78], P = 0.028) but not men (1.70 higher T score [SE 1.74], P = 0.33). The relationships between cerebrovascular function and specific cognitive domains followed a similar pattern, with significant associations present among women but not men., Conclusions: Women with well-controlled HIV may be more vulnerable to the effect of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in people living with HIV should include adequate representation of women and stratification of analyses by sex., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the fact that many coinfections in people with HIV (PWH) are treatable or suppressible, they may still impact neurocognitive (NC) functioning. Here, we aim to evaluate the presence of latent/treated coinfections and their association with NC functioning in a cohort of PWH in Zambia. We carried out a cross-sectional, nested study involving 151 PWH with viral suppression, and a normative sample of 324 adults without HIV. Plasma samples from PWH who underwent a comprehensive NC assessment were evaluated for the presence of treated/latent coinfections that are common in Zambia. Information about treated pulmonary tuberculosis (TB) was obtained from participants' clinical charts. Overall, PWH differed significantly from the HIV seronegatives on all neuropsychological domains except for fine motor control. ANOVA comparisons of all 3 HIV + groups' demographically corrected mean NC T-scores showed that the HIV + /TB + group had the poorest NC functioning in the following domains: executive functioning (F = 4.23, p = 0.02), working memory (F = 5.05, p = 0.002), verbal fluency (F = 4.24, p = 0.006), learning (F = 11.26, p < 0.001), delayed recall (F = 4.56, p = 0.01), and speed of information processing (F = 5.16, p = 0.005); this group also was substantially worse on the total battery (global mean T-scores; F = 8.02, p < 0.001). In conclusion, treated TB coinfection in PWH was associated with worse NC performance compared to both those with antibodies against other coinfections and without. PWH with antibodies for other coinfections (HIV + /CI +) showed somewhat better NC performance compared to those without (HIV + /CI -), which was not expected, although comparisons with the HIV + /CI + group are limited by its lack of specificity regarding type of coinfection being represented., (© 2023. Journal of NeuroVirology, Inc.)

Background and Objectives: To determine whether plasma eicosanoid levels are associated with immune, viral, and cognitive outcomes in people with HIV (PWH)., Methods: We measured 42 eicosanoids in a longitudinal study of 95 PWH and 25 demographically comparable uninfected participants. Routine clinical chemistry, virologic, immune markers, and a neuropsychological test battery assessing 7 cognitive domains were administered to all participants at 2 study visits over an average of 6.5 months., Results: Plasma eicosanoid concentrations were elevated in PWH (n = 95) compared with seronegative controls (n = 25) (100% prediction power at 5% false discovery rate [FDR], α = 0.0531) and were negatively associated with lower current and nadir CD4 lymphocyte counts. Higher levels of eicosanoids were associated with impairments in working memory, verbal fluency, and executive function. Higher plasma viral load was associated with elevated proinflammatory eicosanoids (24% prediction power at 5% FDR and 42.4% prediction power at 10% FDR, α = 0.10). Longitudinal analyses showed that eicosanoid levels were correlated with viral load and with plasma creatinine. Despite associations of eicosanoids with viral loads, elevated plasma eicosanoids were similar in virally suppressed and not fully suppressed PWH., Discussion: These data show that HIV infection is associated with a robust production of eicosanoids that are not substantially reduced by antiretroviral therapy (ART). The sustained elevation of these oxylipins in PWH despite ART may contribute to an accelerated aging phenotype that includes earlier than expected brain and peripheral organ damage., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Benzodiazepine use is linked to neurocognitive impairment (NCI) in the general population and people with HIV (PWH); however, this relationship may depend on age-related factors such as medical comorbidities, which occur at an elevated rate and manifest earlier in PWH. We retrospectively examined whether chronological age or medical burden, a clinical marker for aging, moderated the relationship between benzodiazepine use and NCI in PWH. Participants were 435 PWH on antiretroviral therapy who underwent neurocognitive and medical evaluations, including self-reported current benzodiazepine use. A medical burden index score (proportion of accumulated multisystem deficits) was calculated from 28 medical deficits. Demographically corrected cognitive deficit scores from 15 neuropsychological tests were used to calculate global and domain-specific NCI based on established cut-offs. Logistic regressions separately modeled global and domain-specific NCI as a function of benzodiazepine x age and benzodiazepine x medical burden interactions, adjusting for current affective symptoms and HIV disease characteristics. A statistically significant benzodiazepine x medical burden interaction (p = .006) revealed that current benzodiazepine use increased odds of global NCI only among those who had a high medical burden (index score > 0.3 as indicated by the Johnson-Neyman analysis), which was driven by the domains of processing speed, motor, and verbal fluency. No age x benzodiazepine interactive effects on NCI were present. Findings suggest that the relationship between BZD use and NCI among PWH is specific to those with greater medical burden, which may be a greater risk factor for BZD-related NCI than chronological age., (© 2022. The Author(s).)

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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: We 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)., Methods: A 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., Results: Overall, 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)., Discussion: We 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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Neurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years., Methods: PWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation: (interleukin-6 [IL-6], C-reactive protein [CRP], monocyte chemoattractant protein type 1 [MCP-1], D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor - type II [sTNFR-II], neopterin, and soluble CD40 ligand [sCD40L], oxidative stress (protein carbonyls, 8-oxo-2'-deoxyguanosine [8-oxo-dG]) and altered amyloid processing [amyloid beta (Aβ)-42, soluble amyloid precursor protein-α (sAPPα)] using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline., Results: Participants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other; at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 [4.44, 14.5] years, nadir CD4 104/μL (19,205), current CD4 568/μL (356, 817), and 80.1% had plasma HIV RNA <50 c/mL. Participants were enrolled between 2003 and 2007; median (IQR) duration of follow-up 12.4 [9.69, 16.2] years. Three biomarker factors were identified: Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r ​= ​-0.168, p ​= ​0.0205 and r ​= ​-0.156, p ​= ​0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r ​= ​-0.154, p ​= ​0.0332), while IL-6 did not (r ​= ​-0.109, p ​= ​0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r ​= ​-0.1734, p ​= ​0.0006). Together BDI-II (p ​= ​0.0290), F1 (p ​= ​0.0484) and F3 (p ​= ​0.0309) contributed independently to NC decline (p ​= ​0.0028); their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression., Conclusions: PWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Astrocytes 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)., Methods: We 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., Results: Participants 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., Conclusions: Astrocyte 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.

Older people with HIV (PWH) experience increased risk of age-related neurodegenerative disorders and cognitive decline, such as amnestic mild cognitive impairment (aMCI). The objective of this study was to examine the relationship between aMCI and plasma VEGF biomarkers among older PWH. Data were collected at a university-based research center from 2011 to 2013. Participants were 67 antiretroviral therapy-treated, virally suppressed PWH. Participants completed comprehensive neurobehavioral and neuromedical evaluations. aMCI status was determined using adapted Jak/Bondi criteria, classifying participants as aMCI + if their performance was > 1 SD below the normative mean on at least two of four memory assessments. VEGF family plasma biomarkers (i.e., VEGF, VEGF-C, VEGF-D, and PIGF) were measured by immunoassay. Logistic regression models were conducted to determine whether VEGF biomarkers were associated with aMCI status. Participants were mostly non-Hispanic white (79%) men (85%) with a mean age of 57.7 years. Eighteen (26.9%) participants met criteria for aMCI. Among potential covariates, only antidepressant drug use differed by aMCI status, and was included as a covariate. VEGF-D was significantly lower in the aMCI + group compared to the aMCI - group. No other VEGF levels (VEGF, VEGF-C, PIGF) differed by aMCI classification (ps > .05). In a sample of antiretroviral therapy-treated, virally suppressed PWH, lower levels of VEGF-D were associated with aMCI status. Longitudinal analyses in a larger and more diverse sample are needed to support VEGF-D as a putative biological marker of aMCI in HIV., (© 2021. The Author(s).)

Background: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR)., Objective: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality., Methods: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8 + and CD4 + T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes., Results: IHG-I, tracking high-grade equilibrium between CD8 + and CD4 + T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females., Conclusions: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19., (Published by Elsevier Inc.)

For people living with HIV (PLWH) and sexual minorities (SM), the intersection of identities can compound experiences like stigma and discrimination resulting in poor emotional health. We investigated the separate and interactive associations of HIV serostatus and sexual identity with emotional health. Our dataset included 371 participants. Emotional health was assessed by the NIH Toolbox emotion battery which yields negative affect, social satisfaction, and psychological well-being. Regressions were conducted for each composite, with HIV serostatus, sexual identity, and their interaction as independent variables along with covariates. The HIV serostatus x SM identity interaction was statistically significant in the regression of Negative Affect ( p  =   .01): heterosexuals living with HIV had worse Negative Affect compared to heterosexual HIV-persons ( p  =   .01). The interaction terms were for social satisfaction and psychological well-being were not significant. However, among PLWH, sexual minorities reported better Social Satisfaction ( p  =   .03) and marginally better psychological well-being ( p  =   .07) compared to heterosexuals.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system, mitochondria contribute to neuroinflammation and aging, which may ultimately drive the pathogenesis of neurodegenerative diseases. Mitochondrial DNA (mtDNA) haplogroups are associated with health outcomes in PWH. For example, we previously observed less global NCI in Hispanic ancestry PWH having mtDNA haplogroup B. Another study reported increased NCI among PWH having African subhaplogroup L2a. We therefore analyzed NC domains in relation to these haplogroups in CNS HIV Antiretroviral Therapy Effects Research (CHARTER), a multi-site observational neuro-HIV study. Haplogroups were assigned using mtDNA sequence in 1016 PWH. Outcomes were NCI, defined by domain deficit score and mean T-scores (TS) for seven NC domains. Ancestry-stratified analyses of NC performance included Wilcoxon rank sum, χ 2 , and Fisher's exact tests. Multivariable regression adjusted for NC comorbidity, antiretroviral therapy use, and nadir CD4 + T cells. Among 98 Hispanic ancestry PWH, executive function, learning, and recall performance were better with haplogroup B (N = 17) than other haplogroups. With adjustment for covariates, haplogroup B remained associated with better executive function (p = 0.04) and recall TS (p = 0.03). PWH with haplogroup B had fewer impaired domains than other haplogroups (p < 0.01). Subhaplogroup L2a (N = 89) was associated with greater NCI in learning, recall, and working memory among 478 PWH of African ancestry, and had more impaired domains than other subhaplogroups (p < 0.01). These findings may inform risk stratification for NCI and studies to define mechanisms by which mtDNA variation may influence NCI in PWH., (© 2021. Journal of NeuroVirology, Inc.)

Objective: Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis's anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH., Methods: 263 individuals were categorized into four groups: HIV- non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal-Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count., Results: HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV- non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05)., Conclusions: Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

Methamphetamine (METH) use disorder is highly prevalent among people with HIV (PWH) and is a significant public health problem. HIV and METH use are each associated with immune system dysfunction; however, the combined effects on the immune system are poorly understood. This cross-sectional project measured soluble immune biomarkers in plasma and cerebrospinal fluid (CSF) collected from a control group, people with a history of a METH use disorder (METH+), PWH with no history of METH use disorder (HIV+), and PWH with a history of METH use disorder (HIV+/METH+). HIV, METH, and immune dysfunction can also be associated with affective and cognitive deficits, so we characterized mood and cognition in our participants. Two factor analyses were performed for the plasma and CSF biomarkers. Plasma IL-8, Ccl2, VEGF, and 8-isoprostane loaded onto one factor that was highest in the HIV+/METH+ group ( p < 0.047) reflecting worse inflammation, vascular injury, and oxidative stress. This plasma factor was also negatively correlated with delayed recall (R = -0.49, p = 0.010), which was worst in the HIV+/METH+ group ( p = 0.030 compared to the control group). Overall, these data implicate that combined HIV-1 infection and METH use may exacerbate inflammation, leading to worse cognition.

Background: Human immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity., Methods: We studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay., Results: Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P < .001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean ± SD, 0.361 ± 1.20 vs -0.501 ± 1.11; P = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV- individuals. Worse BBB index values were associated with higher NFL in CSF (r = 0.380, P = .0169)., Conclusions: Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We hypothesized that humoral immunity stimulation in the CNS in HIV-1C patients would be lower than that in HIV-1B due to a defective Tat chemokine dimotif (C30C31) that might influence cellular trafficking and CNS inflammation. Sixty-eight paired CSF and blood samples from people with HIV (PWH), free of CNS opportunistic infections, were included, HIV-1B (n = 27), HIV-1C (n = 26), and HIV negative (n = 25). IgG intrathecal synthesis was assayed using quantitative and qualitative methods. IgG oligoclonal bands (OCB) in CSF were observed in 51% of PWH, comparable between HIV-1B and HIV-1C, as well as the medians of IgG intrathecal synthesis formulas. The group with HIV infection aviremic in CSF and blood showed 75% of OCB. There was a poor positive correlation between the IgG quotient and GDS. The impact of HIV-1 on IgG intrathecal production was not subtype dependent. Low-grade CNS intrathecal IgG production persists in HIV CNS infection even in PWH with CSF and blood HIV RNA controlled., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: HIV infection and methamphetamine dependence (METH) are each associated with inflammation and premature aging, but their impact on biological aging is difficult to measure. Here we examined the impact of HIV and METH on leukocyte telomere lengths (LTL), and the correlations between LTL and other aging biomarkers., Methods: The study was a cross-sectional analysis of 161 individuals categorized by HIV and methamphetamine (METH) dependence status into four groups: HIV-METH- (n = 50), HIV-METH+ (n = 29), HIV + METH- (n = 40), and HIV + METH+ (n = 42). We analyzed the relationships of leukocyte telomere length (telomere to single copy gene [T/S] ratio) with demographic and clinical data as well as a panel of biomarkers of inflammation and endothelial activation measured in blood and cerebrospinal fluid (CSF)., Results: HIV and METH were independently associated with shorter T/S ratio, even after adjusting for demographics and leukocyte count (R 2 = 0·59, p < 0·0001). Higher plasma C-reactive protein (p = 0·0036) and CSF VCAM-1 (p = 0·0080) were also associated with shorter T/S ratio. A shorter T/S ratio was associated with higher risk for cardiovascular disease (p < 0·0001) and stroke (p < 0·0001), worse motor functioning (p = 0·037) and processing speed (p = 0·023), more depressive symptoms (p = 0·013), and higher CSF neurofilament-light (p = 0·003)., Conclusions: HIV and METH dependence were each associated with shorter telomeres. After adjusting for demographics, HIV, and METH, T/S ratio remained associated with aging-related outcomes including neurocognitive impairment, neurodegeneration, risks of cardiovascular disease and stroke. While not establishing causality, this study supports using the T/S ratio as a biomarker for estimating the impact of HIV and comorbidities on long-term health., (Published by Elsevier B.V.)

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The development of novel antiretroviral treatments has led to a significant turning point in the fight against HIV. Although therapy leads to virologic suppression and prolonged life expectancies, HIV-associated neurocognitive disorder (HAND) remains prevalent. While various hypotheses have been proposed to explain this phenomenon, a growing body of literature explores the neurotoxic effects of antiretroviral therapy. Research to date brings into question the potential role of such medications in neurocognitive and neuropsychiatric impairment seen in HIV-positive patients. This review highlights recent findings and controversies in cellular, molecular, and clinical neurotoxicity of antiretrovirals. It explores the pathogenesis of such toxicity and relates it to clinical manifestations in each medication class. The concept of accelerated aging in persons living with HIV (PLWH) as well as potential treatments for HAND are also discussed. Ultimately, this article hopes to educate clinicians and basic scientists about the neurotoxic effects of antiretrovirals and spur future scientific investigation into this important topic. Graphical Abstract.

The transactivator of transcription (Tat) is a key HIV regulatory protein. We aimed to identify the frequency of key polymorphisms in HIV-1C compared with HIV-1B Tat protein, chiefly in the cysteine-, arginine-, and glutamine-rich domains and identify novel point mutations in HIV-1B and C sequences from Southern Brazil. This study was the first to investigate the genetic diversity and point mutations within HIV-1 Tat C in a Brazilian cohort. This was an observational, cross-sectional study, which included sequences of HIV-1B (n = 20) and HIV-1C (n = 21) from Southern Brazil. Additionally, 344 HIV-1C sequences were obtained from the Los Alamos database: 29 from Brazil and 315 from Africa, Asia, and Europe. The frequency of C31S substitution on HIV-1 Tat C in Brazil was 82% vs. 10% in the HIV-1B group (p < 0.0001). The frequency of the R57S substitution among the HIV-1C sequences from Brazil was 74% vs. 20% in HIV-1B (p = 0.004), and that of substitution Q63E in HIV-1C was 80% and 20% in HIV-1B (p < 0.0001). The mutation P60Q was more frequent in HIV-1B than in HIV-1C (55% and 6.12%, respectively, p < 0.0001)). Novel point mutations in the HIV-1C and B Tat functional domains were described. The frequency of C31S and other key point mutations in HIV-1 Tat C in Brazil were similar to those described in Africa, although lower than those in India. The Tat-B and C sequences found in Southern Brazil are consistent with biological differences and have potential implications for HIV-1 subtype pathogenesis.

Background: HIV and malaria are associated with immunological perturbations and neurocognitive disorders even when asymptomatic. However, the effect of asymptomatic malaria (AM) in HIV-infected adults on neurocognitive impairment (NCI) is not well understood. This study investigated the biomarkers of systemic inflammation and neurocognition in dually infected Nigerian adults., Methods: We assessed the HIV and AM status of 269 adults and measured their global and domain-specific neurocognition and depression using standardized measures. Blood levels of sCD14 and sCD163 were also measured., Results: The mean age of the participants (n = 269) was 33 years, 62% were women, and AM among HIV+ and HIV- was similar (36% versus 37%). NCI was found in 23% (62/269) of participants. HIV+/AM+ had a higher prevalence of impaired learning and executive functions and were more depressed than HIV-/AM- or HIV+/AM-. HIV+ with CD4 T-cell counts ≤200/µL were more impaired in the learning domain than those with >200/µL. HIV+/AM+ group had higher levels of sCD14 compared to the other 3 groups and higher levels of sCD163 than the HIV-/AM- group. Higher levels of sCD14 and sCD163 were each associated with NCI. The sCD163 (log10) levels were higher for those with 1+ versus 2+ parasitemia level., Conclusions: HIV and AM coinfection was associated with an increased risk of reduced learning and executive functions, and elevated systemic inflammation. Mood was more depressed in HIV patients with than those without AM. The mechanisms and long-term effects on neurocognition and depression among HIV+/AM+ individuals should be studied because this coinfection is common globally.

Many factors can influence perceptions of successful aging (SA), including social isolation and poor physical health. We hypothesized that social support attenuates the negative effect of plasma D-dimer, a correlate of HIV and aging, on SA. Participants included 230 adults (134 people with HIV; PWH, 96 HIV-), ages 36-65, segregated into age cohorts with up to 5 yearly visits. Multilevel modeling examined longitudinal within-person associations between D-dimer, social support, and SA. Social support moderated the relationship between D-dimer and SA and was significant among PWH and older individuals (ages 56-65), but not HIV- or younger cohorts. This association was significant only at extreme levels of social support, with significant decreases in social support potentiating the negative impact of D-dimer on SA and significant increases in social support facilitating increased SA. Despite declining health, high social support may improve SA in PWH and older adults, and low support may be especially problematic for older adults.