ABSTRACT
BACKGROUND: Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population. OBJECTIVE: To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women. METHODS AND RESULTS: This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αß)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND. CONCLUSIONS: This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND.
Subject(s)
AIDS Dementia Complex/metabolism , HIV Infections/metabolism , Insulin Receptor Substrate Proteins/metabolism , Receptor, Insulin/metabolism , AIDS Dementia Complex/blood , AIDS Dementia Complex/cerebrospinal fluid , Adult , Cross-Sectional Studies , Databases, Factual , Disease Progression , Female , HIV Infections/blood , HIV Infections/cerebrospinal fluid , HIV Seropositivity/metabolism , Humans , Insulin Receptor Substrate Proteins/blood , Insulin Receptor Substrate Proteins/cerebrospinal fluid , Middle Aged , Neuropsychological Tests , Phosphorylation , Receptor, Insulin/blood , Receptor, Insulin/cerebrospinal fluid , Retrospective Studies , Severity of Illness IndexABSTRACT
PURPOSE: Monocyte ingress into the brain during progressive human immunodeficiency virus (HIV-1) infection parallels the severity of cognitive impairments. Although activated monocyte phenotypes emerge in disease, the functional correlates of these cells remain unresolved. EXPERIMENTAL DESIGN: To this end, we studied the proteome of blood-derived monocytes obtained from Hispanic women with the most severe form of HIV-associated neurocognitive disorders, HIV-associated dementia (HAD). Monocytes isolated from peripheral blood mononuclear cells by CD14+ immunoaffinity column chromatography were >95% pure. Cells were recovered from four patients without evidence of cognitive impairment and five with HAD and analyzed by 2-D DIGE and tandem MS. RESULTS: Importantly, ADP ribosylhydrolase, myeloperoxidase, thioredoxin, peroxiredoxin 3, NADPH, and GTPase-activating protein were all downregulated in HAD. In regards to myeloperoxidase, thioredoxin, and peroxiredoxin 3, these changes were validated in an additional cohort of 30 patients by flow cytometry. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that deficits in monocyte antioxidants lead to neuronal damage through the loss of hydrogen peroxide scavenging capabilities; thus exposing neurons to apoptosis-inducing factors. Altered monocyte functions therefore may contribute to the development and progression of cognitive impairment.
Subject(s)
AIDS Dementia Complex/metabolism , Antioxidants/metabolism , Hispanic or Latino , Monocytes/metabolism , Proteome/analysis , AIDS Dementia Complex/blood , AIDS Dementia Complex/pathology , AIDS Dementia Complex/virology , Adult , Chromatography, Affinity , Female , Free Radical Scavengers/metabolism , Humans , Immunologic Techniques , Middle Aged , Monocytes/virology , Peroxidase/metabolism , Peroxiredoxins/metabolism , Thioredoxins/metabolismABSTRACT
Cigarette smoking alters the immune system and may improve cognitive deficits in neuropsychiatric disorders. Smoking prevalence is high in human immunodeficiency virus (HIV)-infected patients; however, its effect on HIV-associated cognitive impairment remains unknown in the era of antiretroviral treatment. The authors examined associations of smoking with viral immune profile and cognitive function in a cohort of HIV-seropositive women. This observational cross-sectional study included 56 women (36 HIV-seropositive and 20 HIV-seronegative) surveyed with a tobacco questionnaire: the Fagerström Test for Nicotine Dependency. Viral immune status was obtained 6 to 12 months before questioned. Neurocognitive testing (NP) assessed verbal memory, frontal/executive function, psychomotor speed, and motor speed. A reference group of HIV-seronegative women was used to calculate standardized z-scores. Cognitive impairment was classified using a modified American Academy of Neurology criteria, adding an asymptomatic group based on NP tests. Statistics included parametric and nonparametric tests. HIV-seropositive women were more likely to report a history of smoking (P = 0.028). Among them, current smoking correlated with higher plasma viral load (P = 0.048), and history of smoking correlated with lower CD4 cell count (P = 0.027). The authors observed no associations between cognitive impairment and either current or past history of smoking and no differences in neurocognitive domain scores between HIV-seropositive and -seronegative women or between those with and without a history of smoking. However, restricting analysis to HIV-seropositives showed a significant better performance on the frontal/executive domain in those with history of smoking. In summary, history of smoking correlated with better frontal/executive cognitive domain performance in HIV-seropositive women and with worse viral immune profile.
Subject(s)
Cognition Disorders/complications , HIV Infections/complications , HIV Infections/psychology , HIV Seropositivity , HIV-1/immunology , Smoking/adverse effects , Adult , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cognition Disorders/virology , Female , HIV-1/metabolism , Humans , Viral Load , Women's HealthABSTRACT
Cognitive impairment remains a major complication of advanced human immunodeficiency virus (HIV) infection despite the widespread use of anti-retroviral therapy. Diagnosis is made by exclusion making biomarkers of great potential use. Thus, we used an integrated proteomics platform to assess cerebrospinal fluid protein profiles from 50 HIV-1 seropositive Hispanic women. Nine of 38 proteins identified were unique in those patients with cognitive impairment (CI). These proteins were linked to cell signaling, structural function, and antioxidant activities. This work highlights, in a preliminary manner, the utility of proteomic profiling for biomarker discovery for HIV-1 associated cognitive dysfunction.
Subject(s)
Cerebrospinal Fluid/metabolism , Cerebrospinal Fluid/virology , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/etiology , HIV Infections/complications , Proteomics , Adult , Cohort Studies , Electrophoresis, Gel, Two-Dimensional , Female , Humans , Male , Mass Spectrometry/methods , Middle Aged , Molecular Sequence Data , Neuropsychological Tests , Viral Load/methodsABSTRACT
Human immunodeficiency virus (HIV)-associated cognitive impairment, a significant cause of morbidity, affects up to 30% of HIV-infected people. Its prevalence doubled as patients began to live longer after the introduction of highly active retroviral therapy. Women are now one of the fastest growing groups with acquired immunodeficiency syndrome (AIDS) in the United States and Puerto Rico, but relatively little is known about the prevalence and characteristics of cognitive dysfunction in HIV-infected women. In this study the authors investigated its prevalence in a group of HIV-1-seropositive Hispanic women in Puerto Rico. Forty-nine women with a nadir CD4 cell count of < or = 500 cells/mm3 were enrolled. Cognitive impairment was defined according to the American Academy of Neurology criteria for HIV dementia as modified to identify an "asymptomatic cognitively impaired" group. Observed prevalence was compared with prevalence in other populations in United States, Europe, and Australia. Differences in clinical markers and neuropsychological test performance among the cohort stratified by cognitive impairment were tested. Cognitive impairment was observed in 77.6% (38/49) of cases; asymptomatic cognitive impairment in 32.7% (16/49); minor cognitive motor disorders in 16.3% (8/49); and HIV-associated dementia (HAD) in 28.6% (14/49). Cognitive impairment did not correlate with age, CD4 cell count, viral load, or treatment modality. The cross-sectional prevalence of HIV-associated cognitive impairment was 77.6% (28.6% for HAD). These findings should enhance awareness of the prevalence of HIV-associated cognitive impairment, both clinically apparent and "asymptomatic," in Hispanic women and lead to improvements in areas such as education and compliance and to reevaluation of treatment interventions.
Subject(s)
Cognition Disorders/etiology , HIV Infections/epidemiology , HIV Infections/psychology , Adult , Cognition Disorders/virology , Cohort Studies , Female , Hispanic or Latino , Humans , Memory , Middle Aged , Prevalence , Puerto Rico/epidemiology , Recognition, Psychology , Wechsler ScalesABSTRACT
The emergence of a subset of circulating monocytes during human immunodeficiency virus type 1 (HIV-1) disease has been shown to correlate with cognitive impairment. Thus, it is hypothesized that diagnostic protein profiles may be obtained from these cells from patients with or at risk for HIV-1-associated dementia (HAD). To address this possibility, we used ProteinChip assays to define a unique monocyte-derived macrophage (MDM) protein fingerprint during HAD and whether it is affected by highly active antiretroviral therapy (HAART). The study included five Hispanic women, one with HAD, two HIV-1-infected without cognitive impairment, and two seronegative controls. All patients were matched by age and immune status. Monocytes were recovered from the peripheral blood leukocytes by Percoll gradient centrifugation and allowed to differentiate in vitro for 7 days. Cell lysates and supernatants were collected from the MDM and analyzed by surface enhanced laser desorption/ionization-time of flight ProteinChip assays. Seven unique protein peaks between 3.0 and 20.0 kDa were found in the HAD MDM sample. Each of these proteins were abrogated after HAART. Additional studies extending this one time point determination would serve to confirm the general utility of MDM protein profiling for the diagnosis and monitoring of HAD.
Subject(s)
AIDS Dementia Complex/genetics , AIDS Dementia Complex/immunology , HIV-1 , Macrophages/physiology , Macrophages/virology , Protein Array Analysis , AIDS Dementia Complex/diagnosis , Adult , Biomarkers , Female , Humans , Macrophages/cytology , Middle Aged , Monocytes/cytology , ProteomicsABSTRACT
En el análisis de los casos detectados de lepra en Cuba durante el período 1972-1987 se observan diferencias significativas en la distribución por formas clínicas relacionadas con el sexo. Los resultados obtenidos de este análisis se presentan en este trabajo, concluyéndose que existe un predominio de las formas multibacilares de lepra en el sexo masculino, lo que pudiera deberse a una mayor resistencia en el sexo femenino
Subject(s)
Adolescent , Adult , Middle Aged , Humans , Male , Female , Age Distribution , Leprosy/epidemiology , Sex Distribution , CubaABSTRACT
En el análisis de los casos detectados de lepra en Cuba durante el período 1972-1987 se observan diferencias significativas en la distribución por formas clínicas relacionadas con el sexo. Los resultados obtenidos de este análisis se presentan en este trabajo, concluyéndose que existe un predominio de las formas multibacilares de lepra en el sexo masculino, lo que pudiera deberse a una mayor resistencia en el sexo femenino
