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Background and ObjectivesTo determine whether plasma eicosanoid levels are associated with immune, viral, and cognitive outcomes in people with HIV (PWH).MethodsWe 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.ResultsPlasma 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.DiscussionThese 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.

Background The risk of severe 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 To examine whether deficits in IR that antedate or are induced by SARS-CoV-2 infection independently predict COVID-19 mortality. Methods IR levels were quantified with two 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 clinical 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 associated with underrepresentation of IHG-I (21%) vs. overrepresentation (77%) of IHG-II or IHG-IV, especially in males vs. females (P Conclusion 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. Clinical implications Biomarkers tracking immunologic resilience may have broad prognostic utility, as they associated with longevity, as well as resistance to a progressive disease course during SARS-CoV-2, influenza, or HIV infection.

Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive irmpairment in people living with HIV (PWH). Data suggest that cardiovascular risk may play a greater role in cognitive health in women than men with HIV.We performed a cross-sectional study of 104 participants with virologically suppressed HIV from two 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.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.Women with well-controlled HIV may be more vulnerable to the impact of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in PWH should include adequate representation of women and stratification of analyses by sex.

Background Cognitive complications persist in persons with HIV (PWH) during suppressive antiretroviral therapy (ART). Low levels of HIV during ART could contribute to these complications. In this study, we measured cerebrospinal fluid (CSF) HIV using a single copy assay (SCA) to investigate a possible relationship between low level HIV and cognition.Design/Methods: SCA data were analyzed from three consecutive paired CSF-plasma specimens collected over a mean of 456 days from 96 participants on suppressive ART. Using mixed models, the presence of CSF HIV by SCA as a risk factor for worse neurocognitive performance was examined. Results At baseline on the SCA, 45.8% of participants had detectable plasma HIV RNA (median 8 copies/milliliter (ml), interquartile range (IQR) = 3-17 among detectable values), and 17.7% had detectable CSF HIV RNA (median CSF concentration= 3 copies/ml, interquartile range= 2-13 among detectable values). The frequency of CSF HIV RNA detection declined over time in CSF (p=0.018) with a trend toward decline in plasma (p=0.064). Detectable CSF HIV RNA during the study was associated with worse performance in the domains of recall (p=0.014) and motor (p=0.040), and a trend with worse overall global performance (p=0.078). Integrase inhibitor use, while very infrequent in this cohort, was associated with better performance in two domains. Conclusions Low-level CSF HIV RNA declines with time but is associated with worse cognitive performance in two domains. Additional research is needed to better understand the relationship between HIV RNA persistence during long-term ART and central nervous system complications in PWH.

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 (allps < .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.

The biological mechanisms underlying emotional distress in HIV infection are likely to be complex but remain understudied. We investigated whether dysbiotic signatures in the gut microbiome of persons living with HIV (PLWH) are associated with their emotional status. We retrospectively examined the gut microbiome and clinical evaluation of 129 adults (94 PLWH and 35 HIV-) enrolled at UC San Diego's HIV Neurobehavioral Research Program. A subset of participants (32 PLWH vs. 13 HIV-) underwent an emotional assessment using the NIH Toolbox Emotion Battery summarized by three composite scores (negative affect, social satisfaction, and psychological well-being). We then sequenced the 16S rDNA V3-V4 regions from stool and performed taxonomic assignment using CLC Microbial Genomics Module. The gut microbiota profiles were evaluated in relation to participants' emotional assessment. All analyses were done in R statistical software. We found that the relative abundance of aerotolerant bacteria was significantly higher in PLWH (p&nbsp

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.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II>22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.

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.

Although plasma D-dimer levels are high in patients with some types of peripheral neuropathy, this has not been examined in people with HIV (PWH). We tested the hypothesis that higher plasma D-dimer levels would be related to the presence and severity of HIV-associated distal sensory peripheral neuropathy (DSP). Participants in a U.S. research cohort were evaluated using standardized clinical examinations and interviews for findings of DSP and distal neuropathic pain by trained clinicians. D-dimer levels in the two neuropathy groups (0 or 1 versus 2 or more neuropathy signs), were compared using the Wilcoxon rank sum test. Multivariable regression assessed the effects of age and other covariates. Participants were 185 PWH, mean (SD) age 56.2 (8.10), 19.7% females, 56.4% non-White, median nadir and current CD4 lymphocytes 107 (IQR 20, 210) and 567 (348, 817), undetectable plasma HIV RNA 79.9%; and 210 people without HIV (PWoH), mean age 50.6 (15.8) years, 38.6% female, 18.1% non-White. Among PWH, 50 had 0 signs, 47 had 1 and 88 had 2 or more; among PWoH, 149 had 0 signs, 38 had 1 sign, and 23 had 2 or more signs (PWH versus PWoH p = 1.36e-20). Log10 plasma D-dimer levels were higher in PWH than PWoH (2.78±0.233 versus 2.66±0.253, p = 5.20e-6). D-dimer was significantly higher in those with DSP (2 or more DSP signs) compared to those without (p = 0.0017, Wilcoxon rank sum test). In multivariable analyses this relationship was independent of potential confounders. This association persisted in a sensitivity analysis that was limited to only the subset of participants with undetectable plasma HIV RNA (Wilcoxon p = 0.041). In PWoH, d-dimer levels were numerically higher in those with DSP (2.75±0.206 versus 2.65±0.256, p = 0.0604). Neuropathy symptoms (pain, paresthesias) were not significantly related to D-dimer levels. Since DSP is a major cause of disability in PWH, identifying biomarkers such as D-dimer may enable future investigations to assess prognosis or response to therapy.

OBJECTIVE HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition. METHODS Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores. RESULTS HIV significantly interacted with METH (P < 0.001) such that compared with HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d = 0.96; HIV-/METH+: d = 0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d = 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r = -0.19), learning (r = -0.23), and delayed recall (r = -0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH- groups (ie, HIV-/METH- and HIV+/METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV-/METH+, HIV+/METH+). DISCUSSION HIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

HIV infection and drug use intersect epidemiologically, and their combination can result in complex effects on brain and behavior. The extent to which drugs affect the health of persons with HIV (PWH) depends on many factors including drug characteristics, use patterns, stage of HIV disease and its treatment, comorbid factors, and age. To consider the range of drug effects, we have selected two that are in common use by PWH: methamphetamine and cannabis. We compare the effects of methamphetamine with those of cannabis, to illustrate how substances may potentiate, worsen, or even buffer the effects of HIV on the CNS. Data from human, animal, and ex vivo studies provide insights into how these drugs have differing effects on the persistent inflammatory state that characterizes HIV infection, including effects on viral replication, immune activation, mitochondrial function, gut permeability, blood brain barrier integrity, glia and neuronal signaling. Moving forward, we consider how these mechanistic insights may inform interventions to improve brain outcomes in PWH. This review summarizes literature from clinical and preclinical studies demonstrating the adverse effects of METH, as well as the potentially beneficial effects of cannabis, on the interacting systemic (e.g., gut barrier leakage/microbial translocation, immune activation, inflammation) and CNS-specific (e.g., glial activation/neuroinflammation, neural injury, mitochondrial toxicity/oxidative stress) mechanisms underlying HIV-associated neurocognitive disorders.

Author(s): Ferrara, Micol; Bumpus, Namandje N; Ma, Qing; Ellis, Ronald J; Soontornniyomkij, Virawudh; Fields, Jerel A; Bharti, Ajay; Achim, Cristian L; Moore, David J; Letendre, Scott L | Abstract: ObjectiveDetermine concentrations of antiretroviral therapy (ART) drugs in the human brain.DesignCohort study of persons with HIV who consented to antemortem assessment and postmortem autopsy.MethodsEleven persons with HIV who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated. Autopsies were performed within 24 h of death and brain tissue was stored at -80 °C. Concentrations of 11 ART drugs were measured in three brain regions (globus pallidus, cortical gray matter, white matter) by HPLC tandem mass spectrometry with a lower limit of quantification of 25 ng/ml.ResultsParticipants were mostly men (82%) with a mean age of 40.4 years. Drug concentrations in brain tissue were highly variable and exceeded published concentrations in cerebrospinal fluid for several drugs, including for tenofovir, efavirenz, and lopinavir. Drug concentrations correlated most strongly between cortical gray matter and globus pallidus (rho = 0.70) but less well between globus pallidus and white matter (rho = 0.43). Combining all drugs and brain regions (n = 89), higher drug concentrations in brain were associated with longer estimated duration of HIV infection (P = 0.015), lower HIV RNA in plasma (P = 0.0001), lower nadir CD4 T-cell count (P = 0.053), and worse neurocognitive performance (P = 0.017).ConclusionThis is the first analysis of ART drug concentrations in human brain tissue. Concentrations of several drugs in this analysis were similar to published concentrations in cerebrospinal fluid but others exceeded published concentrations. The association between higher drug concentrations in the brain and worse neurocognitive performance may indicate ART neurotoxicity.

We examined how the discrepancy between felt age (FA) and chronological age (CA) differed by HIV serostatus across three age cohorts and related to health-related quality of life (HRQoL). Participants included 119 people living with HIV (PLWH) and 98 uninfected adults, ages 36–65 years. FA was assessed by asking, “How old/young do you feel?” HRQoL was measured using the Medical Outcome Study Short Form Health Survey. Linear regressions examined the interaction between HIV serostatus and HRQoL on FA discrepancy scores (FADS; i.e., difference between CA and FA). 72.3% of PLWH felt younger than their CA, which was lower than the uninfected group (92.9%; p < .001). PLWH had lower FADS than the uninfected group (p = .050), particularly in the 46- to 55-year-old cohort (p = .015). The positive association between physical HRQoL and FADS was stronger among PLWH (β = 0.14, p = .024). A high proportion of PLWH reported feeling younger than their CA, and this perception was related to higher physical HRQoL.

This study evaluated whether a history of lifetime methamphetamine (MA) use disorder increases risk for poor sleep quality in people with or without HIV infection (HIV+/HIV-). Participants (n = 313) were stratified into four groups based on HIV status and lifetime MA use disorder diagnosis [HIV+/MA+ (n = 84); HIV+/MA- (n = 141); HIV-/MA+ (n = 16); and HIV-/MA- (n = 72)] and compared on global sleep outcomes using the Pittsburgh Sleep Quality Index (PSQI). Significant differences on global sleep were observed between HIV+/MA+ and HIV+/MA- groups, but not between the HIV- groups. Follow-up multiple regression analyses within the HIV+ subgroups examined global sleep scores as a function of MA status and clinical covariates, including those related to HIV disease and demographics. HIV+ individuals with a history of MA use disorder evidenced significantly poorer sleep quality and were more likely to be classified as problematic sleepers than those without a lifetime disorder. This was independent of depressed mood, body mass index, and viral suppression while on treatment. Poorer reported sleep quality among HIV+/MA+ was associated also with multiple adverse functional outcomes, including greater objective cognitive impairment, unemployment, clinical ratings of functional impairment, and self-reported cognitive difficulties, decreased independence in activities of daily living, and poorer overall life quality. Interventions to avoid or curtail MA use in HIV+ individuals may help protect sleep quality and improve functioning.

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

BACKGROUND: The aims of this study were: investigate the frequency of HIV-1 RNA levels discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients HIV-1 subtype C on antiretroviral therapy; evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group; and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. METHODS: HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. RESULTS: CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p < 0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of >5cells/mm(3) than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15 cells/mm(3)) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance, was 83%, and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher, than those for a HIV(−) person. CONCLUSION: Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

Suppression of plasma HIV RNA is most often attainable with effective antiretroviral therapy. Despite this, in some individuals, detection of HIV RNA remains evident in the cerebrospinal fluid (CSF) which is generally termed CSF HIV RNA escape. Defining CSF HIV RNA escape from a virological point of view, a symptomatology point of view and its management has many challenges with several different definitions being utilized. In this editorial, we outline proposed consensus definitions of CSF HIV RNA escape with consideration of virological, symptomatology and management aspects of this condition.

OBJECTIVE The aim of this study was to measure the protein concentration and biological activity of HIV-1 Tat in cerebrospinal fluid (CSF) of individuals on suppressive antiretroviral therapy (ART). DESIGN CSF was collected from 68 HIV-positive individuals on ART with plasma viral load less than 40 copies/ml, and from 25 HIV-negative healthy controls. Duration of HIV infection ranged from 4 to more than 30 years. METHODS Tat levels in CSF were evaluated by an ELISA. Tat protein and viral RNA were quantified from exosomes isolated from CSF, followed by western blot or quantitative reverse transcription PCR, respectively. Functional activity of Tat was assessed using an LTR transactivation assay. RESULTS Tat protein was detected in 36.8% of CSF samples from HIV-positive patients. CSF Tat concentration increased in four out of five individuals after initiation of therapy, indicating that Tat was not inhibited by ART. Similarly, exosomes from 34.4% of CSF samples were strongly positive for Tat protein and/or TAR RNA. Exosomal Tat retained transactivation activity in a CEM-LTR reporter assay in 66.7% of samples assayed, which indicates that over half of the Tat present in CSF is functional. Presence of Tat in CSF was highly associated with previous abuse of psychostimulants (cocaine or amphetamines; P = 0.01) and worse performance in the psychomotor speed (P = 0.04) and information processing (P = 0.02) cognitive domains. CONCLUSION Tat and TAR are produced in the central nervous system despite adequate ART and are packaged into CSF exosomes. Tat remains biologically active within this compartment. These studies suggest that Tat may be a quantifiable marker of the viral reservoir and highlight a need for new therapies that directly inhibit Tat.

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.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.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 RNA50 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.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.

PURPOSE OF REVIEW: Cognitive impairment and depression continue to be common among people with HIV (PWH) in the combination antiretroviral therapy (ART) era. A better understanding of the biological mechanisms that may underpin these disorders is needed. The purpose of this review is to describe published findings on soluble biomarkers from blood and cerebrospinal fluid (CSF) that have been associated with either cognition or depression among PWH in the setting of ART. RECENT FINDINGS: Several biomarkers, including those that reflect viral persistence, monocyte/macrophage activation, and other processes, are associated with cognition and depressive symptoms. Some but not all results have been consistent across multiple studies. More research has been published on biomarkers of cognition relative to biomarkers of depression (particularly from CSF). SUMMARY: More studies are needed that investigate multiple biomarkers to understand the role of distinct but additive pathways in these disorders and to guide the development of new therapies.

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.

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.