Impairment In HIV-positive Patients Research Articles

HIV-1 Tat Primes and Activates Microglial NLRP3 Inflammasome-Mediated Neuroinflammation.

Neuroinflammation associated with HIV-1 infection is a problem affecting ∼50% of HIV-infected individuals. NLR family pyrin domain containing 3 (NLRP3) inflammasome has been implicated in HIV-induced microglial activation, but the mechanism(s) remain unclear. Because HIV-1 Transactivator of Transcription (Tat) protein continues to be present despite antiretroviral therapy and activates NF-kB, we hypothesized that Tat could prime the NLRP3 inflammasome. We found a dose- and time-dependent induction of NLRP3 expression in microglia exposed to Tat compared with control. Tat exposure also time-dependently increased the mature caspase-1 and IL-1β levels and enhanced the IL-1β secretion. These in vitro findings were validated in archival brain tissues from Simian Immunodeficiency Virus (SIV)-infected and uninfected rhesus macaques. Further validation of NLRP3 priming in vivo involved administration of lipopolysaccharide (LPS) to HIV transgenic (Tg) rats followed by assessment of IL-1β mRNA expression and inflammasome activation (ASC oligomers and mature IL-1β). Intriguingly, LPS potentiated upregulation of IL-1β mRNA and inflammasome activation in HIV-Tg rats compared with the wild-type controls. Interestingly, we found an inverse relationship in the expression of NLRP3 and its negative regulator, miR-223, suggesting a miR-223-mediated mechanism for Tat-induced NLRP3 priming. Furthermore, blockade of NLRP3 resulted in decreased IL-1β secretion. Collectively, these findings suggest a novel role of Tat in priming and activating the NLRP3 inflammasome. Therefore, NLRP3 can be envisioned as a therapeutic target for ameliorating Tat-mediated neuroinflammation.SIGNIFICANCE STATEMENT Despite successful suppression of viremia with increased longevity in the era of combined antiretroviral therapy, chronic inflammation with underlying neurocognitive impairment continues to afflict almost 50% of infected individuals. Viral, bacterial, and cellular products have all been implicated in promoting the chronic inflammation found in these individuals. Understanding the molecular mechanism(s) by which viral proteins such as HIV-1 Transactivator of Transcription (Tat) protein can activate microglia is thus of paramount importance. Herein, we demonstrate a novel role of Tat in priming and activating NLR family pyrin domain containing 3 (NLRP3) inflammasomes in microglial cells and in HIV-Tg rats administered lipopolysaccharide. Targeting NLRP3 inflammasome pathway mediators could thus be developed as therapeutic interventions to alleviate or prevent neuroinflammation and subsequent cognitive impairment in HIV-positive patients.

Utility of a brief computerized battery to assess HIV-associated neurocognitive impairment in a resource-limited setting.

Despite the persistently high prevalence of neurocognitive impairment in HIV-positive patients, routine HIV care in many resource-limited settings does not include neuropsychological assessment. The objective of this study was to examine the utility of a brief computerized battery for identifying neurocognitive impairment in a busy HIV clinic in Uganda. Specifically, we compared performance on a gold standard neuropsychological exam to that on the CogState Brief Battery. In this cross-sectional study, 181 HIV-positive patients completed both assessment batteries in a randomized order. The primary outcome measures were neurocognitive impairment on the standard exam defined by the global deficit score and cumulative performance on the CogState Brief Battery. Sixty-nine participants (38%) were classified as impaired on the standard neuropsychological exam, and participants who were classified as impaired performed significantly worse on CogState compared to those who were unimpaired (p < 0.001). CogState had adequate specificity but low sensitivity, suggesting that it may not be a clinically useful screening tool to identify patients who likely have neurocognitive impairment in Uganda. This study supports the feasibility of using a computerized battery for assessing neurocognitive impairment in HIV-positive patients in resource-limited settings, but additional research is needed to identify screening tools with higher sensitivity for use in HIV clinics.

Depression and diagnosis of neurocognitive impairment in HIV-positive patients.

Neurocognitive impairment (NCI) is frequently observed in patients infected with human immunodeficiency virus (HIV) and results from the compromise of subcortical brain structures by the virus. The manifestations of NCI range from asymptomatic impairment to dementia. In addition to cognitive impairment resulting from HIV infection, other factors such as depression are associated with the loss of cognitive functions. The aim of this study was to estimate the prevalence of NCI in HIV-positive patients in a city in southern Brazil and to establish possible associations for the prevalence of NCI with HIV-related and other risk factors. This cross-sectional study of HIV-positive outpatients was conducted in a specialized care service in the city of Pelotas in Southern Brazil. Sociodemographic data and HIV-related information were collected, and all patients underwent psychiatric and neurocognitive evaluations. The prevalence of NCI among the 392 patients was 54.1% when tracked using the IHDS (International HIV Dementia Scale) and 36.2% when the IHDS was associated with a battery of complementary tests. A bivariate analysis suggested an association of NCI with gender, age, educational level, depression, current CD4 count and lowest CD4 count. The association of NCI with depression remained in the Poisson regression (PR=1.96, 95%CI=1.12-3.42). The prevalence of cognitive impairment in HIV-positive patients estimated in this study is in accordance with international and Brazilian data. Of the factors analyzed, depression showed the greatest evidence of association with neurocognitive loss. Based on our findings, the inclusion of instruments to evaluate depression in our services for patients with HIV and acquired immunodeficiency syndrome (AIDS) is recommended.

Intellectual Impairment in Patients with Newly Diagnosed HIV Infection in Southwestern Nigeria.

Neurocognitive impairment is a detrimental complication of HIV infection. Here, we characterized the intellectual performance of patients with newly diagnosed HIV infection in southwestern Nigeria. We conducted a prospective study at Owo Federal Medical Center by using the adapted Wechsler Adult Intelligence Scale (WAIS). The raw scores were converted to standardized scores (z-scores) and correlated with clinical and laboratory findings. Fifty-eight HIV positive patients were recruited; 72% were in WHO stages 3 and 4. We detected a high rate of intellectual impairment in HIV positive patients and controls (63.8% and 10%, resp.; P < 0.001). HIV positive patients performed worse throughout the subtests of both verbal and performance intelligence quotients. Presence of opportunistic infections was associated with worse performance in the similarities and digit symbol tests and performance and full scale scores. Lower body weight correlated with poor performance in different WAIS subtests. The high rate of advanced disease stage warrants measures aimed at earlier diagnosis and treatment. Assessment of neurocognitive performance at diagnosis may offer the opportunity to improve functioning in daily life and counteract disease progression.

The Montreal Cognitive Assessment: A Pilot Study of a Brief Screening Tool for Mild and Moderate Cognitive Impairment in HIV-Positive Veterans.

HIV-associated neurocognitive disorders (HANDs) are common, often go undetected, and can impact treatment outcomes. There is limited evidence on how to perform routine cognitive screening in HIV clinical settings. To address this, 44 HIV-positive males were recruited from a Veteran Affairs Infectious Disease clinic and completed the Montreal Cognitive Assessment (MoCA), International HIV Dementia Scale (IHDS), and Depression Anxiety and Stress Scale-21. In all, 50% scored below the MoCA cutoff and 36% scored below the IHDS cutoff. Current CD4 was the strongest predictor of an abnormal MoCA score (P = .007, 95% confidence interval [CI]: 0.987-0.998) and elevated depression was the second strongest predictor (P = .008, CI: 1.043-1.326). Combination antiviral therapy use and age were not significant predictors in this model. The MoCA appeared to be a reasonable screening tool to detect cognitive impairment in HIV-positive patients, and although it is not sufficient to diagnose HAND, it has the potential to provide meaningful clinical data.

Symptoms of depression and rates of neurocognitive impairment in HIV positive patients in Beijing, China

BackgroundIn China an estimated 780,000 people are living with HIV (PLWH). In high-income countries PLWH are at increased risk of depression, with subsequent adverse consequences for quality of life, and HIV-related morbidity and mortality. There are few data from low-and middle-income countries. The aims of this country-specific investigation of the Asia Pacific NeuroAIDS Consortium (APNAC) study were to establish the point prevalence, severity and HIV-related and non-HIV related correlates of depressive symptoms in PLWH, in Beijing, China. MethodPLWH attending an outpatient clinic at Ditan Hospital, Beijing were recruited consecutively. Data sources were: study-specific questions about demographic characteristics, and health behaviours, the Centre for Epidemiological Studies Depression Scale (CES-D), the World Health Organisation Self-Reporting Questionnaire (SRQ-20) translated into Mandarin and administered as structured individual interviews, and a screen battery of four standard neuropsychological tests. ResultsIn total 50/51 (98%) eligible patients agreed to participate. Overall 28% scored CES-D≥16 or SRQ20≥10 and 18% in these clinical ranges on both measures; 69% were classified as being neuropsychologically impaired (scoring below 1 SD of the control value on at least two tests). Higher depressive symptom scores were associated with lower education, alcohol overuse and diminished motor ability (all p<0.05), but not neuropsychological impairment ConclusionClinically significant depressive symptoms among this cohort of PLWH in Beijing occurred at 5 times the rate reported among a general Chinese urban population. No participants had been assessed for depression prior to the study and none were treated, indicating that consideration of psychological morbidity and its consequences for health behaviours should be incorporated into routine HIV care in China.

Routine detection and management of neurocognitive impairment in HIV-positive patients in a UK centre

SummaryWe estimated the burden of HIV-associated neurocognitive disorders (HAND) in a UK clinic. From a random sample, and referrals to specialist services over one year (neurology, clinical psychology, hospital admissions), we determined whether patients were diagnosed with HIV-associated dementia (HAD) and whether they reported symptoms suggesting neurocognitive impairment (NCI). In the first sample, 2/150 (prevalence 1.3%; 95% confidence interval [CI] 0.2–4.7%) had documented HAD. Eleven patients (7.3%; CI 3.7–12.7%) reported recent symptoms suggesting NCI; most of these individuals were diagnosed with a psychiatric or substance-use disorder. Among specialist referrals with symptoms suggesting NCI, 11 were diagnosed with HAD from a clinic population of 3129 individuals (annual incidence 0.4%; CI 0.2–0.6%). No patients with mildly symptomatic or asymptomatic HAND were identified in either sample, suggesting that such patients remain undetected in current clinical practice. Evidence-based screening for HAND in HIV clinics may be needed.

Successful Treatment of Epstein–Barr Virus Encephalitis in the Setting of HIV-Associated Neurocognitive Disorder: A Diagnostic and Therapeutic Challenge

We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein-Barr virus (EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected in the cerebrospinal fluid and brain biopsy, which also demonstrated histopathological findings consistent with the diagnosis. This occurred on the background of a 12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was required to reach the diagnosis in this case, highlighting the importance of thorough investigation of neurological impairment in HIV-positive patients. Clinicopathological recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir.

Available evidence does not support serosorting as an HIV risk reduction strategy

Recent data highlighted the association between penetration of antiretrovirals in the central nervous system (CNS) and neurocognitive impairment in HIVpositive patients. Existing antiretrovirals have been ranked according to a score of neuropenetration, which was shown to be a predictor of anti-HIVactivity in the CNS and improvement of neurocognitive disorders [1]. Main factors affecting drug penetration are known to be protein binding, lipophilicity and molecular weight [2]. Moreover, active translation by membrane transporters (such as p-glycoprotein) could be a key mechanism of passage [3]. The use of raltegravir (RGV), a novel antiretroviral drug targeted to inhibit the HIV preintegrase complex, is increasing worldwide due to its efficacy and tolerability. However, penetration of RGV in the CNS has not been yet elucidated. In fact, prediction of RGV neuropenetration according to molecular characteristics is controversial. Intermediate protein binding (83%) and large volume of distribution (273 l) could suggest a high distribution beyond extracellular spaces [4]. On the contrary, low lipophilicity (oil/water partition coefficient at pH 7.4 of 2.80) and intermediate molecular weight (482.51 Da) suggest a limited diffusion. Furthermore, in-vitro studies suggest that RGV is substrate of p-glycoprotein, although this efflux pump has not been identified to significantly affect plasma pharmacokinetics [5]. In any case, no data concerning RGV passage into cerebrospinal fluid of animals or humans have yet been published.

Motor Function and Human Immunodeficiency Virus–Associated Cognitive Impairment in a Highly Active Antiretroviral Therapy–Era Cohort

Cognitive impairment has long been recognized as a manifestation of human immunodeficiency virus (HIV) infection. However, highly active antiretroviral therapy (HAART) has altered the neurologic manifestations of HIV. To develop a measure to quantify the motor abnormalities included in the original descriptions of HIV-associated dementia (HAD); to determine whether motor, affective, and behavioral dysfunction predict cognitive impairment; and to determine whether quantitative motor testing is a helpful adjunct in the diagnosis of HAD in a complex population from the HAART era. Neurologic and neuropsychological data were collected from the Manhattan HIV Brain Bank, a longitudinal cohort study of patients with advanced HIV. The HIV-Dementia Motor Scale (HDMS) was developed and validated and cognitive and affective or behavioral function was quantified using global neuropsychological T scores, the Beck Depression Inventory (BDI), and an independent assessment of apathy. Relationships among cognitive, motor, affective, and behavioral performance were examined using correlation, linear regression, and analyses of variance. An urban AIDS research center. A total of 260 HIV-positive, predominantly minority patients. The HDMS scores and global neuropsychological T scores. The HDMS and BDI scores were independent predictors of cognitive impairment. Significant cognitive impairment was found in patients with motor dysfunction. Patients diagnosed as having HAD had a greater degree of motor impairment than those with other neurocognitive diagnoses. Motor, affective, and behavioral abnormalities predict cognitive impairment in HIV-positive patients in this HAART-era cohort. The HDMS may be useful in the assignment of HIV-associated neurocognitive impairment in HIV populations in which normative data or neuropsychological test design is not optimal.

The relationship between AIDS retinal cotton wool spots and neuropsychological impairment in HIV-positive individuals in the pre-highly active antiretroviral therapy era

Purpose: To determine the relationship between AIDS retinal cotton wool spots (CWS) and neuropsychological impairment in HIV-positive individuals in the pre-HAART (highly active antiretroviral therapy) era and the association between AIDS-related retinal CWS and neuropsychological impairment in HIV-positive patients not treated with HAART. Methods: A case-control analysis of prospectively acquired data in HIV-infected individuals who underwent prospective and longitudinal evaluations of retinal findings as well as neuropsychological testing was performed. Individuals underwent prospective retinal ophthalmic examinations with fundus photography of any retinal lesions. They also underwent periodic neuropsychological testing. The occurrence of retinal CWS was analyzed in relationship to neuropsychological impairment. Results: Thirty individuals with CWS were compared to 60 matched control AIDS patients. There was no association between either global clinical neuropsychological impairment or impairment in any of the five major domains tested and retinal CWS. There was an association between beta-2 microglobulin and CWS as well as an association between low CD4 T-cell count and the presence of retinal CWS. Conclusions: We found no association between retinovascular disease and neurocognitive impairment in this case-control study. Retinal CWS in HIV disease are related to higher serum beta-2 microglobulin levels and lower CD4 T-cell counts, suggesting that these lesions are related to HIV disease progression but may be caused by a pathological process independent of CNS disease.

Vagal system impairment in HIV-positive patients with chronic hepatitis C: has hepatic glutathione deficiency a pathogenetic role?

Vagal system impairment in HIV-positive patients with chronic hepatitis C: has hepatic glutathione deficiency a pathogenetic role?