Metabolic Syndrome and Neurocognitive Deficits in HIV Infection.

BACKGROUND: The adverse consequences of HIV and related comorbidities on the central nervous system remain prevalent in the era of combination antiretroviral therapy. Metabolic syndrome (MetS) is a common comorbidity in HIV and has been linked to increased neurocognitive impairment in the general population. We investigated the association between MetS and neurocognition among persons living with HIV (PLHIV). METHODS: Participants included 109 PLHIV and 92 HIV-uninfected adults (HIV-) from the Multi-dimensional Successful Aging cohort study at the University of California San Diego (age: M = 50.8, SD = 8.0). Participants completed neuromedical, psychiatric, and neurocognitive assessments. Based on a comprehensive neurocognitive battery, we examined global neurocognitive deficits (based on the entire battery) and neurocognitive deficits in 7 domains (verbal fluency, learning, recall, executive function, working memory, speed of information processing, and fine motor skills). MetS was determined via the standard criteria by the National Cholesterol Education Program's Adult Treatment Panel-III. Covariates examined included demographics and psychiatric comorbidities (and HIV disease characteristics among PLHIV). RESULTS: MetS had an independent significant effect on global neurocognitive deficits among PLHIV (P = 0.03) but not among their HIV- counterparts (P = 0.93). Among PLHIV, MetS was most strongly associated with the neurocognitive domains of learning, fine motor skills, and executive function. Diabetes and elevated triglycerides were the MetS components most strongly linked with increased global neurocognitive deficits in PLHIV. CONCLUSIONS: The present findings underscore the need for early identification of PLHIV at risk for MetS and the implementation of preventive and treatment approaches to lessen the development of MetS and neurocognitive impairment among PLHIV.

Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge.

Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe2+ and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe2+ and inhibited by divalent-chelating agents. flaR mutant was highly susceptible to H2O2 compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally, flaR mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR's roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.

Differences in Neurocognitive Impairment Among HIV-Infected Latinos in the United States.

OBJECTIVES: Human immunodeficiency virus (HIV) disproportionately affects Hispanics/Latinos in the United States, yet little is known about neurocognitive impairment (NCI) in this group. We compared the rates of NCI in large well-characterized samples of HIV-infected (HIV+) Latinos and (non-Latino) Whites, and examined HIV-associated NCI among subgroups of Latinos. METHODS: Participants included English-speaking HIV+ adults assessed at six U.S. medical centers (194 Latinos, 600 Whites). For overall group, age: M=42.65 years, SD=8.93; 86% male; education: M=13.17, SD=2.73; 54% had acquired immunodeficiency syndrome. NCI was assessed with a comprehensive test battery with normative corrections for age, education and gender. Covariates examined included HIV-disease characteristics, comorbidities, and genetic ancestry. RESULTS: Compared with Whites, Latinos had higher rates of global NCI (42% vs. 54%), and domain NCI in executive function, learning, recall, working memory, and processing speed. Latinos also fared worse than Whites on current and historical HIV-disease characteristics, and nadir CD4 partially mediated ethnic differences in NCI. Yet, Latinos continued to have more global NCI [odds ratio (OR)=1.59; 95% confidence interval (CI)=1.13-2.23; p<.01] after adjusting for significant covariates. Higher rates of global NCI were observed with Puerto Rican (n=60; 71%) versus Mexican (n=79, 44%) origin/descent; this disparity persisted in models adjusting for significant covariates (OR=2.40; CI=1.11-5.29; p=.03). CONCLUSIONS: HIV+ Latinos, especially of Puerto Rican (vs. Mexican) origin/descent had increased rates of NCI compared with Whites. Differences in rates of NCI were not completely explained by worse HIV-disease characteristics, neurocognitive comorbidities, or genetic ancestry. Future studies should explore culturally relevant psychosocial, biomedical, and genetic factors that might explain these disparities and inform the development of targeted interventions. (JINS, 2018, 24, 163-175).

Portable lactate analyzer for measuring lactate in cerebrospinal fluid (CSF) and plasma - method-comparison evaluations.

UNLABELLED: Increased plasma lactate levels can indicate the presence of metabolic disorders in HIV infected individuals. OBJECTIVE: To determine whether a portable analyzer is valid for measuring cerebrospinal fluid (CSF) and plasma lactate levels in HIV infected individuals. METHOD: CSF and plasma were collected from 178 subjects. Samples tested by the Accutrend portable analyzer were compared to those tested by a reference device (SYNCHRON LX 20). RESULTS: The portable analyzer had in plasma sensitivity of 0.95 and specificity 0.87. For CSF the specificity was 0.95; the sensitivity 0.33; the negative predictive value was 95% and the positive predictive value 33%. CONCLUSIONS: These findings support the validity of the portable analyzer in measuring lactate concentrations in CSF that fall within the normal range. The relatively poor positive predictive value indicates that a result above the reference range may represent a "false positive test", and should be confirmed by the reference device before concluding abnormality.

Portable lactate analyzer for measuring lactate in cerebrospinal fluid (CSF) and plasma ? method-comparison evaluations / Analisador portátil para dosar lactato no líquido cefalorraquidiano e plasma ? comparação de método

Increased plasma lactate levels can indicate the presence of metabolic disorders in HIV infected individuals. Objective: To determine whether a portable analyzer is valid for measuring cerebrospinal fluid (CSF) and plasma lactate levels in HIV infected individuals. Method: CSF and plasma were collected from 178 subjects. Samples tested by the Accutrend® portable analyzer were compared to those tested by a reference device (SYNCHRON LX® 20). Results: The portable analyzer had in plasma sensitivity of 0.95 and specificity 0.87. For CSF the specificity was 0.95; the sensitivity 0.33; the negative predictive value was 95% and the positive predictive value 33%. Conclusions: These findings support the validity of the portable analyzer in measuring lactate concentrations in CSF that fall within the normal range. The relatively poor positive predictive value indicates that a result above the reference range may represent a “false positive test”, and should be confirmed by the reference device before concluding abnormality. .

O aumento da concentração plasmática dos níveis de lactato pode indicar a presença de distúrbios metabólicos em indivíduos infectados pelo HIV. Objetivo: Determinar a validade do analisador portátil para quantificar os níveis de lactato no líquido cefalorraquidiano (LCR) e plasma em indivíduos infectados. Método: LCR e plasma foram coletados de 178 participantes. As amostras testadas com o analisador portátil Accutrend® e os resultados comparados com aqueles obtidos com o equipamento de referência (SYNCHRON LX® 20). Resultados: O analisador portátil teve, no plasma, sensibilidade de 0,95 e especificidade 0,87. No LCR a especificidade foi 0,95; a sensibilidade 0,33; o valor preditivo negativo foi de 95% e o valor preditivo positivo 33%. Conclusões: Estes dados suportam a validade dos resultados do analisador portátil em concentrações de lactato dentro da faixa normal. Os valores preditivos positivos relativamente baixos indicam que um resultado acima da faixa de referência pode representar um resultado “falso positivo”. .

A phase I study of folate immune therapy (EC90 vaccine administered with GPI-0100 adjuvant followed by EC17) in patients with renal cell carcinoma.

This is the first phase I, open-label study to assess the safety, pharmacokinetics, and antitumor activity of a novel immunotherapeutic regimen known as Folate Immune (EC90 vaccine administered with GPI-0100 adjuvant followed by EC17, a folate-targeted hapten immunotherapy that targets folate receptor expressing cancer cells), which is designed to convert poorly immunogenic tumors to highly immunogenic tumors in patients with metastatic renal cell carcinoma. Three to 6 patients were enrolled in each cohort. In the vaccination phase, patients were given once weekly vaccinations of 0.2 mg of EC90 plus 3.0 mg of GPI-0100 for 3-5 weeks. In the treatment phase, patients were treated with 0.031, 0.092, or 0.276 mg/kg of EC17, 5 d/wk, for weeks 3, 4, or 6. Forty-one patients were enrolled in the study of which 33 patients received ≥1 treatment of EC17. Two dose-limiting toxicities were observed including grade 4 anaphylaxis and grade 3 pancreatitis. During the vaccination phase, mild to moderate injection site reactions were the most frequently reported adverse events. During the treatment phase, transient hypersensitivity reactions were the most common adverse event. Partial response was noted in 4% (1/28) of patients, and stable disease was noted in 54% (15/28) of patients after cycle 1 and was maintained in the majority of patients entering the extension phase of the study. EC90 vaccine with GPI-0100 adjuvant followed by EC17 is safe and well tolerated. The recommended regimen for further studies is 4 weekly vaccinations with 0.2 mg of EC90 plus 3.0 mg GPI-0100 followed by treatment with 0.3 mg of EC17.

Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer.

Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest-growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized <50 years old (young) and >50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule-associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients.

Clinical variables identify seronegative HCV co-infection in HIV-infected individuals.

BACKGROUND: A substantial number of people living with HIV (PLWH) are co-infected with Hepatitis C Virus (HCV) but have a negative screening HCV antibody test (seronegative HCV infection, or SN-HCV). OBJECTIVE: To identify a concise set of clinical variables that could be used to improve case finding for SN-HCV co-infection among PLWH. STUDY DESIGN: Two hundred HIV-infected participants of the CHARTER study were selected based on 7 clinical variables associated with HCV infection but were HCV seronegative. Data were analyzed using Fisher's exact tests, receiver-operating characteristic (ROC) curves, and logistic regression. RESULTS: Twenty-six (13%) participants had detectable HCV RNA. SN-HCV was associated with a history of IDU, elevated ALT and AST, low platelets, black ethnicity, and undetectable HIV RNA in plasma. Each of these clinical variables, except for abnormal AST, remained independently associated with SN-HCV in a multivariate logistic regression analysis. A composite risk score correctly identified SN-HCV with sensitivity up to 85% and specificity up to 88%. CONCLUSIONS: In a substantial minority of PLWH, seronegative HCV viremia can be predicted by a small number of clinical variables. These findings, after validation in an unselected cohort, could help focus screening in those at highest risk.

The prevalence and incidence of neurocognitive impairment in the HAART era.

OBJECTIVES: HAART suppresses HIV viral replication and restores immune function. The effects of HAART on neurological disease are less well understood. The aim of this study was to assess the prevalence and incidence of neurocognitive impairment in individuals who initiated HAART as part of an AIDS clinical trial. DESIGN: A prospective cohort study of HIV-positive patients enrolled in randomized antiretroviral trials, the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study. METHODS: We examined the association between baseline and demographic characteristics and neurocognitive impairment among 1160 subjects enrolled in the ALLRT study. RESULTS: A history of immunosuppression (nadir CD4 cell count < 200 cells/microl) was associated with an increase in prevalent neurocognitive impairment. There were no significant virological and immunological predictors of incident neurocognitive impairment. Current immune status (low CD4 cell count) was associated with sustained prevalent impairment. CONCLUSION: The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression. The association of sustained impairment with worse current immune status (low CD4 cell count) suggests that restoring immunocompetence increases the likelihood of neurocognitive recovery. Finally, the lack of association between incident neurocognitive impairment and virological and immunological indicators implies that neural injury continues in some patients regardless of the success of antiretroviral therapy on these laboratory measures.

Human immunodeficiency virus and the central nervous system.

The pandemic of HIV/AIDS continues to grow daily. Incident cases among women, intravenous drug users and ethnic minorities comprise the fastest growing segment of the HIV-infected population, and the number of HIV-infected individuals over the age of 50 is growing rapidly. Today, the central nervous system and the immune system are seen as main targets of HIV infection. Significant progress in the knowledge and treatment of AIDS has been obtained in recent years. The neurological manifestations directly related to HIV are acute viral meningitis, chronic meningitis, HIV-associated dementia (HAD), vacuolar myelopathy, and involvement of the peripheral nervous system.

Human immunodeficiency virus and the central nervous system

The pandemic of HIV/AIDS continues to grow daily. Incident cases among women, intravenous drug users and ethnic minorities comprise the fastest growing segment of the HIV-infected population, and the number of HIV-infected individuals over the age of 50 is growing rapidly. Today, the central nervous system and the immune system are seen as main targets of HIV infection. Significant progress in the knowledge and treatment of AIDS has been obtained in recent years. The neurological manifestations directly related to HIV are acute viral meningitis, chronic meningitis, HIV-associated dementia (HAD), vacuolar myelopathy, and involvement of the peripheral nervous system.

Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV.

INTRODUCTION: Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF). METHODS: LPV was measured by liquid chromatography/mass spectrometry in 31 CSF-plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 microg/l. RESULTS: Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 microg/l (range, < 3.7 to 608; typical trough values approximately 4000 microg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 microg/l [interquartile range (IQR), 4805-9620] and all CSF samples had measurable LPV concentrations: median 17.0 microg/l (IQR, 12.1-22.7). The median CSF-plasma ratio was 0.23% (range, 0.12-0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus. CONCLUSIONS: In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.