Imaging of Brain Structural and Functional Effects in People With Human Immunodeficiency Virus.

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting "Biotypes of CNS Complications in People Living with HIV," held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH.

Contemporary trends in HIV-associated neurocognitive disorders in Ghana.

BACKGROUND: Widespread introduction of early combination antiretroviral therapy (cART) for People Living with HIV (PLWH) will influence the burden, profile, and trajectory of HIV-associated neurocognitive disorders (HAND) in the 21st century. OBJECTIVES: To assess the prevalence and trajectory of HAND among PLWH in a Ghanaian tertiary medical center. METHODS: We analyzed the dataset of a study involving PLWH established on cART (n = 256) and PLWH not initially on cART (n = 244). HIV-negative individuals (n = 246) served as normative controls for neurocognitive assessments. HAND was defined according to the Frascati criteria into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia (HAD) at enrollment and at month 12. Multivariate logistic regression models were fitted to identify factors associated with HAND. RESULTS: Among PLWH on cART, 21.5%, 3.5% and 0.0% had ANI, MND and HAD respectively compared with 20.1%, 9.8% and 2.0% among PLWH cART naïve, p < 0.0001. Overall, 71.6%, 20.8%, 6.6% and 1.0% had no cognitive impairment, ANI, MND and HAD at baseline. Among participants who completed month 12 follow-up, 55.2% had no cognitive impairment, 43.5%, 1.2%, 0.0% had ANI, MND and HAD respectively, p < 0.0001. Adjusted odds ratio (95% CI) of six independent predictors of HAND at month 12 were no education (3.29;1.81-6.00), stage 4 disease (4.64;1.37-15.69), hypertension (2.28;1.10-4.73), nevirapine use (2.05;1.04-4.05), baseline viral load (0.66;0.56-0.77), and cigarette use (0.10; 0.03-0.42). CONCLUSION: Most Ghanaian patients in the post-cART era with HAND had mild neurocognitive impairments. The impact of hypertension on progression of HAND warrants further evaluation in our settings.

Beneficial and Adverse Effects of cART Affect Neurocognitive Function in HIV-1 Infection: Balancing Viral Suppression against Neuronal Stress and Injury.

HIV-associated neurocognitive disorders (HAND) persist despite the successful introduction of combination antiretroviral therapy (cART). While insufficient concentration of certain antiretrovirals (ARV) may lead to incomplete viral suppression in the brain, many ARVs are found to cause neuropsychiatric adverse effects, indicating their penetration into the central nervous system (CNS). Several lines of evidence suggest shared critical roles of oxidative and endoplasmic reticulum stress, compromised neuronal energy homeostasis, and autophagy in the promotion of neuronal dysfunction associated with both HIV-1 infection and long-term cART or ARV use. As the lifespans of HIV patients are increased, unique challenges have surfaced. Longer lives convey prolonged exposure of the CNS to viral toxins, neurotoxic ARVs, polypharmacy with prescribed or illicit drug use, and age-related diseases. All of these factors can contribute to increased risks for the development of neuropsychiatric conditions and cognitive impairment, which can significantly impact patient well-being, cART adherence, and overall health outcome. Strategies to increase the penetration of cART into the brain to lower viral toxicity may detrimentally increase ARV neurotoxicity and neuropsychiatric adverse effects. As clinicians attempt to control peripheral viremia in an aging population of HIV-infected patients, they must navigate an increasingly complex myriad of comorbidities, pharmacogenetics, drug-drug interactions, and psychiatric and cognitive dysfunction. Here we review in comparison to the neuropathological effects of HIV-1 the available information on neuropsychiatric adverse effects and neurotoxicity of clinically used ARV and cART. It appears altogether that future cART aiming at controlling HIV-1 in the CNS and preventing HAND will require an intricate balancing act of suppressing viral replication while minimizing neurotoxicity, impairment of neurocognition, and neuropsychiatric adverse effects. Graphical abstract Schematic summary of the effects exerted on the brain and neurocognitive function by HIV-1 infection, comorbidities, psychostimulatory, illicit drugs, therapeutic drugs, such as antiretrovirals, the resulting polypharmacy and aging, as well as the potential interactions of all these factors.

Inhibition of the Dead Box RNA Helicase 3 Prevents HIV-1 Tat and Cocaine-Induced Neurotoxicity by Targeting Microglia Activation.

HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins, including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly influences the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. From the identified high priority genes, we narrowed the list to those with known small molecule ligands developed for other applications and lacking systemic toxicity in animal models. To validate the AI-based process, the selective small molecule inhibitor of DDX3 helicase activity, RK-33, was chosen and tested for neuroprotective activity. The compound, previously developed for cancer treatment, was tested for the prevention of combined neurotoxicity of HIV Tat and cocaine. Rodent cortical cultures were treated with 6 or 60 ng/ml of HIV Tat and 10 or 25 µM of cocaine, which caused substantial toxicity. RK-33 at doses as low as 1 µM greatly reduced the neurotoxicity of Tat and cocaine. Transcriptome analysis showed that most Tat-activated transcripts are microglia-specific genes and that RK-33 blocks their activation. Treatment with RK-33 inhibits the Tat and cocaine-dependent increase in the number and size of microglia and the proinflammatory cytokines IL-6, TNF-α, MCP-1/CCL2, MIP-2, IL-1α and IL-1ß. These findings reveal that inhibition of DDX3 may have the potential to treat not only HAND but other neurodegenerative diseases. Graphical Abstract RK-33, selective inhibitor of Dead Box RNA helicase 3 (DDX3) protects neurons from combined Tat and cocaine neurotoxicity by inhibition of microglia activation and production of proinflammatory cytokines.

Selective Estrogen Receptor ß Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders.

The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor ß agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n = 5 and 80%, n = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era. Graphical Abstract HIV-1 transgenic (Tg) and control animals were treated with either 0.2 mg S-Equol (SE) or placebo between 2 and 3 months of age (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). Neurocognitive assessments, tapping preattentive processes, stimulus response learning, sustained attention and selective attention, were conducted to evaluate the utility of SE as a therapeutic for HIV-1 associated neurocognitive disorders (HAND). Planned comparisons between HIV-1 Tg and control animals treated with placebo were utilized to establish a genotype effect, revealing prominent neurocognitive impairments (NCI) in the HIV-1 Tg rat across all domains. Furthermore, to establish the utility of SE, HIV-1 Tg animals treated with SE were compared to control animals treated with placebo. Treatment with 0.2 mg SE ameliorated NCI, to levels that were indistinguishable from controls, in at least a subset (i.e., 50-100%) of HIV-1 Tg animals. Thus, SE supports an efficacious, adjunctive therapeutic for HAND.

Bidirectional Associations among Nicotine and Tobacco Smoke, NeuroHIV, and Antiretroviral Therapy.

People living with HIV (PLWH) in the antiretroviral therapy (ART) era may lose more life-years to tobacco use than to HIV. Yet, smoking rates are more than twice as high among PLWH than the general population, contributing not just to mortality but to other adverse health outcomes, including neurocognitive deficits (neuroHIV). There is growing evidence that synergy with chronic inflammation and immune dysregulation that persists despite ART may be one mechanism by which tobacco smoking contributes to neuroHIV. This review will summarize the differential effects of nicotine vs tobacco smoking on inflammation in addition to the effects of tobacco smoke components on HIV disease progression. We will also discuss biomarkers of inflammation via neuroimaging as well as biomarkers of nicotine dependence (e.g., nicotine metabolite ratio). Tobacco smoking and nicotine may impact ART drug metabolism and conversely, certain ARTs may impact nicotine metabolism. Thus, we will review these bidirectional relationships and how they may contribute to neuroHIV and other adverse outcomes. We will also discuss the effects of tobacco use on the interaction between peripheral organs (lungs, heart, kidney) and subsequent CNS function in the context of HIV. Lastly, given the dramatic rise in the use of electronic nicotine delivery systems, we will discuss the implications of vaping on these processes. Despite the growing recognition of the importance of addressing tobacco use among PLWH, more research is necessary at both the preclinical and clinical level to disentangle the potentially synergistic effects of tobacco use, nicotine, HIV, cognition and immune dysregulation, as well as identify optimal approaches to reduce tobacco use. Graphical Abstract Proposed model of the relationships among HIV, ART, smoking, inflammation, and neurocognition. Solid lines represent relationships supported by evidence. Dashed lines represent relationships for which there is not enough evidence to make a conclusion. (a) HIV infection produces elevated levels of inflammation even among virally suppressed individuals. (b) HIV is associated with deficits in cognition function. (c) Smoking rates are higher among PLWH, compared to the general population. (d) The nicotine metabolite ratio (NMR) is associated with smoking behavior. (e) HIV and tobacco use are both associated with higher rates of psychiatric comorbidities, such as depression, and elevated levels of chronic stress. These factors may represent other mechanisms linking HIV and tobacco use. (f) The relationship between nicotine, tobacco smoking, and inflammation is complex, but it is well-established that smoking induces inflammation; the evidence for nicotine as anti-inflammatory is supported in some studies, but not others. (g) The relationship between tobacco use and neurocognition may differ for the effects of nicotine (acute nicotine use may have beneficial effects) vs. tobacco smoking (chronic use may impair cognition). (h) Elevated levels of inflammation may be associated with deficits in cognition. (i) PLWH may metabolize nicotine faster than those without HIV; the mechanism is not yet known and the finding needs validation in larger samples. We also hypothesize that if HIV-infection increases nicotine metabolism, then we should observe an attenuation effect once ART is initiated. (j) It is possible that the increase in NMR is due to ART effects on CYP2A6. (k) We hypothesize that faster nicotine metabolism may result in higher levels of inflammation since nicotine has anti-inflammatory properties.

Symptomatic cerebrospinal fluid escape.

: Cerebrospinal fluid (CSF) viral escape is defined by detectable HIV-RNA in CSF despite undetectable or lower-than-CSF level in plasma of patients receiving combination antiretroviral therapy (cART). This condition may occasionally be associated with neurological problems, consisting of new and progressive cognitive decline and/or focal symptoms and signs, defining the 'symptomatic CSF escape'. Brain MRI usually shows diffuse white matter hyperintensities that recall the presentation of HIV encephalopathy in the precART era. However, patients develop symptomatic CSF escape with relatively high CD4 cell counts and suppressed or low systemic virus replication. In addition, the frequent CSF pleocytosis and the pathological demonstration of CD8 T-cell brain infiltrates in some cases of symptomatic escape indicate that inflammation is an important component in the pathogenesis of this condition. Low nadir CD4 cells are common, likely reflecting the establishment of a HIV reservoir in the central nervous system (CNS). CSF escape seems to result from reactivation of CNS infection when cART potency is lowered, because of low patient's adherence, drug resistance, or use of drug combinations that are poorly effective in the CNS and cART optimization is key to revert escape and neurological disease in the great majority of cases.

The impact of HIV central nervous system persistence on pathogenesis.

: The persistence of HIV in the central nervous system is somewhat controversial particularly in the context of HIV viral suppression from combined antiretroviral therapy. Further, its significance in relation to HIV pathogenesis in the context of HIV-associated neurocognitive disorders, systemic HIV pathogenesis, and eradication in general, but especially from the brain, are even more contentious. This review will discuss each of these aspects in detail, highlighting new data, particularly from recent conference presentations.

Plasma Cystatin C Associates With HIV-Associated Neurocognitive Disorder but Is a Poor Diagnostic Marker in Antiretroviral Therapy-Treated Individuals.

OBJECTIVE: To examine associations between plasma cystatin C and neurocognitive impairment (NCI) and its performance as a diagnostic marker before and during initial antiretroviral therapy (ART). METHODS: Multivariable logistic regression and generalized estimating equations examined associations with NCI, determined by neuropsychological measurements, in participants of a 48-week randomized clinical trial of initial ART. Receiver operator characteristic curves examined diagnostic models of NCI. RESULTS: Cystatin C was associated with NCI before ART [odds ratio (OR) 3.4 (95% CI: 1.2 to 9.4) for each 2-fold increase in baseline levels] and during 48 weeks of ART, in models that excluded baseline measurements [OR 3.0 (1.2 to 7.8) for each 2-fold increase in time-updated levels]. The strength of association increased with more severe impairment using HIV-associated neurocognitive disorder criteria [OR 2.2 (0.8 to 6.0) with asymptomatic NCI and OR 4.0 (1.5 to 11.0) with mild neurocognitive disorder or HIV-associated dementia vs. no impairment, for each 2-fold increase in time-updated levels] or by global development score [OR 2.6 (1.1 to 6.3) with mild impairment and OR 4.6 (1.1 to 18.9) with moderate or severe impairment vs. no impairment]. Cystatin C performed poorly as a diagnostic marker for NCI, however, with an area under the receiver operator characteristic curve of 0.58 at baseline and 0.54 at week 48. CONCLUSIONS: Higher plasma cystatin C levels were significantly associated with NCI, but these levels did not seem to be useful as a diagnostic marker for this condition.

Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice.

OBJECTIVE: Almost half of HIV-positive people on antiretroviral therapy have demonstrable mild neurocognitive impairment (HIV-NCI), even when virologically suppressed. Intranasal insulin therapy improves cognition in Alzheimer's disease and diabetes. Here we tested intranasal insulin therapy in a model of HIV-NCI in EcoHIV-infected conventional mice. DESIGN AND METHODS: Insulin pharmacokinetics following intranasal administration to mice was determined by ELISA. Mice were inoculated with EcoHIV to cause NCI; 23 days or 3 months after infection they were treated daily for 9 days with intranasal insulin (2.4 IU/mouse) and examined for NCI in behavioral tests and HIV burdens by quantitative PCR. Some animals were tested for hippocampal neuronal integrity by immunostaining and expression of neuronal function-related genes by real time-quantitative PCR. The effect of insulin treatment discontinuation on cognition and neuropathology was also examined. RESULTS: Intranasal insulin administration to mice resulted in µIU/ml levels of insulin in cerebrospinal fluid with a half-life of about 2 h, resembling pharmacokinetic parameters of patients receiving 40 IU. Intranasal insulin treatment starting 23 days or 3 months after infection completely reversed NCI in mice. Murine NCI correlated with reductions in hippocampal dendritic arbors and downregulation of neuronal function genes; intranasal insulin reversed these changes coincident with restoration of cognitive acuity, but they returned within 24 h of treatment cessation. Intranasal insulin treatment reduced brain HIV DNA when started 23 but not 90 days after infection. CONCLUSION: Our preclinical studies support the use of intranasal insulin administration for treatment of HIV-NCI and suggest that some dendritic injury in this condition is reversible.

Association Between Cognitive Tests and Antiretroviral Medication Adherence in Older Adults With HIV.

BACKGROUND: One of the fastest growing populations living with HIV is older adults especially those 65 years of age or older. Current antiretroviral therapy (ART) has prolonged life expectancy of persons with HIV. However, for therapy to be effective, patients need to be adherent. Over time, older persons with HIV may experience HIV-associated neurocognitive disorders or other factors that could affect ART adherence. The use of expedient cognitive tests that help measure medication adherence may be useful for the optimal care of these patients. OBJECTIVE: To investigate the association between cognitive tests and ART adherence. METHODS: This was a prospective study evaluating patients 65 years of age or older with HIV. Cognitive tests used included the Executive Clock-Drawing Task (CLOX) 1 and 2, Trail Making Test parts A and B, and Grooved Pegboard Test (GPB). The medication event monitoring system cap over 1 month was used as the primary measure for adherence. RESULTS: CLOX 1 and GPB were significantly related to adherence ( P < 0.05). Comparison of the magnitude of each measure's relation to adherence suggests that the GPB is a better indicator of ability to adhere ( R = 0.514 vs R = 0.381). Conclusion and Relevance: CLOX 1 and GPB demonstrated an association with adherence in patients 65 years of age or older with HIV. Although the use of these tests to measure adherence in older persons with HIV seems promising, more research is needed to ascertain their ultimate utility.

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS.

Nicotine, one of the key active ingredients in tobacco smoke, exerts its effects via binding to nicotinic acetylcholine receptors (nAChRs). Although both negative and positive pharmacological effects of nicotine have been shown in numerous animals and human studies, its interaction with human immunodeficiency virus-1 (HIV-1) have not been fully elucidated. Even though combined anti-retroviral therapy (cART) limits the progression of HIV-1 to acquired immune deficiency syndrome (AIDS), HIV-associated neurocognitive disorders (HAND) remain prevalent. There is thus a compelling need to enhance our understanding of HAND-related neurologic dysfunction. Some biochemical pathways and physiological dysfunctions have been found to be shared by HAND and Alzheimer's (AD) or Parkinson's (PD) diseases, and nicotine may exert the same neuroprotection in HAND that has been observed in both AD and PD. In the past dozen years, various potential therapeutic effects of nicotine such as neuroprotection have been revealed in both in vivo and in vitro studies, including using HIV-1 transgenic (HIV-1Tg) rat model, which mimics HIV-infected patients receiving cART. In the current review, we describe recent progress in the prevalence of HIV/AIDS with and without cigarette smoking, some animal models for studying neural dysfunction associated with HIV-1 infection, elucidating the modulatory effects of cigarette smoking/nicotine on HIV/AIDS, the anti-inflammatory effects of nicotine, and the neuroprotective effects observed in HIV-1Tg rat model. Taken together, these findings suggest the following: although tobacco smoking does cause deleterious effects in both health and disease conditions such as HIV infection, nicotine, the significant component of tobacco smoke, has been shown to possess some neuroprotective effects in HIV patients, possible via its anti-inflammatory activities. It is therefore necessary to study nicotine's dual effects on neuroHIV/neuroAIDS in hope of better defining the potential medical uses of nicotine or its analogues, and to make them available in a purer and less dangerous form.

Alterations in brain TREM2 and Amyloid-ß levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-ß, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aß protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aß levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aß in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aß and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Comparison of two screening tests for HIV-Associated Neurocognitive Disorder suspected Japanese patients with respect to cART usage.

In this study, we demonstrated the pervasiveness of HIV-associated neurocognitive disorders (HAND) among a selection of Japanese patients as well as evaluated and compared the Mini Mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS) for use as a screening tool among combination anti-retroviral therapy (cART)-naïve and cART experienced patients. The MMSE and the IHDS have both been used as HAND screening tests around the world with variable success. It has been reported the increased usage of cART the utility of these screening tests may have been diminished due to the decreased severity of impairment and the altered pattern of neurocognitive impairments in cART era HAND patients. It is therefore possible the MMSE and the IHDS may still be useful among cART-naïve patients even in the cART era. However, only one study has investigated and compared the screening results of the IHDS among cART-naïve and cART experienced patients. All HIV positive patients who visited, or were admitted, to the Ryukyu University Hospital between January 2009 and March 2014 were evaluated for inclusion. Selected patients (n = 49) had data without omission for all tests. The overall prevalence of HAND in our cohort was 44%. The area under the curve (AUC), for all subjects using the MMSE and the IHDS, were 0.60 and 0.69, respectively. However, the AUC among cART-naïve patients were 0.58 and 0.76 for the MMSE and the IHDS, respectively. Whereas, cART experienced patients had an AUC of 0.60 and 0.61, respectively. Overall, the MMSE demonstrated a poor screening ability for HAND, regardless of cART usage (the cut-off value of 27 had a Youden's J-Index of 0.1, in all groups). Alternatively, the IHDS was moderately useful for HAND screening among cART-naïve patients (the cut-off value of 11 had a Youden's J-Index of 0.4), but performed poorly as a screening test among cART experienced patients (the cut-off value of 11 had a Youden's J-Index of 0.1).

Multicenter European Prevalence Study of Neurocognitive Impairment and Associated Factors in HIV Positive Patients.

We conducted a cross-sectional study in 448 HIV positive patients attending five European outpatient clinics to determine prevalence of and factors associated with neurocognitive impairment (NCI) using computerized and pen-and-paper neuropsychological tests. NCI was defined as a normalized Z score ≤-1 in at least 2 out of 5 cognitive domains. Participants' mean age was 45.8 years; 84% male; 87% white; 56% university educated; median CD4 count 550 cells/mm3; 89% on antiretroviral therapy. 156 (35%) participants had NCI, among whom 26 (17%; 5.8% overall) reported a decline in activities of daily living. Prevalence of NCI was lower in those always able to afford basic needs (adjusted prevalence ratio [aPR] 0.71, 95% confidence interval [CI] 0.54-0.94) or with a university education (aPR 0.72, 95% CI 0.54-0.97) and higher in those with severe depressive symptoms (aPR 1.53, 95% CI 1.09-2.14) or a significant comorbid condition (aPR 1.40, 95% CI 1.03-1.90).

RESUMEN: Reportamos un estudio de tipo corte transversal que incluye 448 pacientes VIH seropositivos vistos en cinco clínicas especializadas en Europa con el objetivo de medir la prevalencia del trastorno neurocognitivo asociado al VIH (NCI por sus siglas en inglés) y los factores de riesgo asociados a éste. Se usaron pruebas neuropsicológicas computarizadas y en papel para determinar la presencia de NCI, definido como puntuación Z ≤ 1 en al menos 2 de los 5 dominios cognitivos evaluados. La media de edad de los pacientes fue 45,8 años, 84% eran hombres, 87% blancos y 56% tenían educación universitaria. La media de CD4 fue de 550 cel/mm3 y 89% de los pacientes recibían terapia antiretroviral. Un total de 156 (35%) participantes tenían NCI, de los cuales 26 (17%, 5,8% de la población de estudio) reportaron deterioro en actividades de la vida diaria. La prevalencia de NCI fue menor en participantes capaces de cubrir sus necesidades básicas (Razón de prevalencia ajustada [aPR] 0,71; Intervalo de confianza del 95% [95% CI] 0,54-0,94) o con educación universitaria (aPR 0,72; 95%CI 0,54-0,97) pero fue mayor en aquellos con síntomas de depresión severa (aPR 1,53; 95%CI 1,09-2,14) o alguna comorbilidad importante (aPR 1,40; 95%CI 1,03-1,90).

Humanized mice: models for evaluating NeuroHIV and cure strategies.

While the human immunodeficiency virus (HIV) epidemic was initially characterized by a high prevalence of severe and widespread neurological pathologies, the development of better treatments to suppress viremia over years and even decades has mitigated many of the severe neurological pathologies previously observed. Despite effective treatment, mild neurocognitive impairment and premature cognitive aging are observed in HIV-infected individuals, suggesting a changing but ongoing role of HIV infection in the central nervous system (CNS). Although current therapies are effective in suppressing viremia, they are not curative and patients must remain on life-long treatment or risk recrudescence of virus. Important for the development and evaluation of a cure for HIV will be animal models that recapitulate critical aspects of infection in vivo. In the following, we seek to summarize some of the recent developments in humanized mouse models and their usefulness in modeling HIV infection of the CNS and HIV cure strategies.

HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency.

Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.

Can Biomarkers Advance HIV Research and Care in the Antiretroviral Therapy Era?

Despite achieving human immunodeficiency virus type 1 (HIV-1) RNA suppression below levels of detection and, for most, improved CD4+ T-cell counts, those aging with HIV experience excess low-level inflammation, hypercoagulability, and immune dysfunction (chronic inflammation), compared with demographically and behaviorally similar uninfected individuals. A host of biomarkers that are linked to chronic inflammation are also associated with HIV-associated non-AIDS-defining events, including cardiovascular disease, many forms of cancer, liver disease, renal disease, neurocognitive decline, and osteoporosis. Furthermore, chronic HIV infection may interact with long-term treatment toxicity and weight gain after ART initiation. These observations suggest that future biomarker-guided discovery and treatment may require attention to multiple biomarkers and, possibly, weighted indices. We are clinical trialists, epidemiologists, pragmatic trialists, and translational scientists. Together, we offer an operational definition of a biomarker and consider how biomarkers might facilitate progress along the translational pathway from therapeutic discovery to intervention trials and clinical management among people aging with or without HIV infection.

An SIV/macaque model targeted to study HIV-associated neurocognitive disorders.

Simian immunodeficiency virus (SIV) infection of pigtailed macaques is a highly representative and well-characterized animal model for HIV neuropathogenesis studies that provides an excellent opportunity to study and develop prognostic markers of HIV-associated neurocognitive disorders (HAND) for HIV-infected individuals. SIV studies can be performed in a controlled setting that enhances reproducibility and offers high-translational value. Similar to observations in HIV-infected patients receiving antiretroviral therapy (ART), ongoing neurodegeneration and inflammation are present in SIV-infected pigtailed macaques treated with suppressive ART. By developing quantitative viral outgrowth assays that measure both CD4+ T cells and macrophages harboring replication competent SIV as well as a highly sensitive mouse-based viral outgrowth assay, we have positioned the SIV/pigtailed macaque model to advance our understanding of latent cellular reservoirs, including potential CNS reservoirs, to promote HIV cure. In addition to contributing to our understanding of the pathogenesis of HAND, the SIV/pigtailed macaque model also provides an excellent opportunity to test innovative approaches to eliminate the latent HIV reservoir in the brain.

Brain-specific HIV Nef identified in multiple patients with neurological disease.

HIV-1 Nef is a flexible, multifunctional protein with several cellular targets that is required for pathogenicity of the virus. This protein maintains a high degree of genetic variation among intra- and inter-host isolates. HIV Nef is relevant to HIV-associated neurological diseases (HAND) in patients treated with combined antiretroviral therapy because of the protein's role in promoting survival and migration of infected brain macrophages. In this study, we analyzed 2020 HIV Nef sequences derived from 22 different tissues and 31 subjects using a novel computational approach. This approach combines statistical regression and evolved neural networks (ENNs) to classify brain sequences based on the physical and chemical characteristics of functional Nef domains. Based on training, testing, and validation data, the method successfully classified brain Nef sequences at 84.5% and provided informative features for further examination. These included physicochemical features associated with the Src-homology-3 binding domain, the Nef loop (including the AP-2 Binding region), and a cytokine-binding domain. Non-brain sequences from patients with HIV-associated neurological disease were frequently classified as brain, suggesting that the approach could indicate neurological risk using blood-derived virus or for the development of biomarkers for use in assay systems aimed at drug efficacy studies for the treatment of HIV-associated neurological diseases.