The effect of relaxation interventions on cortisol levels in HIV-seropositive women.

PURPOSE: Activation of the hypothalamic-pituitary-adrenal axis, assessed in terms of cortisol levels, may enhance the ability of HIV to infect lymphocytes and downregulate the immune system, accelerating disease progression. This study sought to determine the effects of relaxation techniques on cortisol levels in HIV-seropositive women. METHODS: Women (n = 150) were randomized to a group cognitive-behavioral stress management (CBSM) condition or an individual information condition and underwent 3 types of relaxation training (progressive muscle relaxation, imagery, and autogenic training). Cortisol levels were obtained pre- and postrelaxation. RESULTS: Guided imagery was effective in reducing cortisol in the group condition (t = 3.90, P < .001), and muscle relaxation reduced cortisol in the individual condition (t = 3.1 I, P = .012). Among participants in the group condition attending all sessions, the magnitude of pre- to postsession reduction became greater over time. CONCLUSIONS: Results suggest that specific relaxation techniques may be partially responsible for cortisol decreases associated with relaxation and CBSM.

Vitamin D rescues impaired Mycobacterium tuberculosis-mediated tumor necrosis factor release in macrophages of HIV-seropositive individuals through an enhanced Toll-like receptor signaling pathway in vitro.

Mycobacterium tuberculosis disease represents an enormous global health problem, with exceptionally high morbidity and mortality in HIV-seropositive (HIV(+)) persons. Alveolar macrophages from HIV(+) persons demonstrate specific and targeted impairment of critical host cell responses, including impaired M. tuberculosis-mediated tumor necrosis factor (TNF) release and macrophage apoptosis. Vitamin D may promote anti-M. tuberculosis responses through upregulation of macrophage NO, NADPH oxidase, cathelicidin, and autophagy mechanisms, but whether vitamin D promotes anti-M. tuberculosis mechanisms in HIV(+) macrophages is not known. In the current study, human macrophages exposed to M. tuberculosis demonstrated robust release of TNF, IκB degradation, and NF-κB nuclear translocation, and these responses were independent of vitamin D pretreatment. In marked contrast, HIV(+) U1 human macrophages exposed to M. tuberculosis demonstrated very low TNF release and no significant IκB degradation or NF-κB nuclear translocation, whereas vitamin D pretreatment restored these critical responses. The vitamin D-mediated restored responses were dependent in part on macrophage CD14 expression. Importantly, similar response patterns were observed with clinically relevant human alveolar macrophages from healthy individuals and asymptomatic HIV(+) persons at high clinical risk of M. tuberculosis infection. Taken together with the observation that local bronchoalveolar lavage fluid (BALF) levels of vitamin D are severely deficient in HIV(+) persons, the data from this study demonstrate that exogenous vitamin D can selectively rescue impaired critical innate immune responses in vitro in alveolar macrophages from HIV(+) persons at risk for M. tuberculosis disease, supporting a potential role for exogenous vitamin D as a therapeutic adjuvant in M. tuberculosis infection in HIV(+) persons.

Vitamin D3 supplementation scheme in HIV-infected patients based upon pharmacokinetic modelling of 25-hydroxycholecalciferol.

AIMS: Vitamin D deficiency is prevalent in HIV-infected patients and has been associated with osteopenia and HIV disease progression. Our aims were to investigate the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D], the effect of antiretroviral treatment (ARV) and others factors that may influence the pharmacokinetics, and to determine a vitamin D3 dosing scheme to reach the 30 ng ml(-1) threshold (defined as 25(OH)D sufficiency). METHODS: This monocentric retrospective study included 422 HIV-infected patients aged 16 to 85 years. A total of 723 25(OH)D concentrations were available for pharmacokinetic evaluation and a population pharmacokinetic model was developed with MONOLIX 3.2. RESULTS: Median 25(OH)D at baseline was 16 ng ml(-1) (interquartile range 11-23 ng ml(-1)) for the total population, 17% of patient had concentrations below 10 ng ml(-1), 68% between 10 and 30 ng ml(-1) and 15% above 30 ng ml(-1). 25(OH)D pharmacokinetics were best described by a one compartment model with an additional endogenous production. The effects of season and skin phototype were significant on production rate. The endogenous production was 20% lower in non-white skin phototype patients and was decreased by 16% during autumn, winter and spring. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs (ARV). To obtain concentrations between 30 and 80 ng ml(-1), the dosing recommendation was 100,000 IU every month. CONCLUSIONS: Season and skin phototype had an influence on the endogenous production of 25(OH)D. However no effect of ARV was found. A dosing scheme to reach sufficient 25(OH)D concentrations is proposed.

Neuropsychological function and cerebral metabolites in HIV-infected youth.

The effects of HIV on brain metabolites and cognitive function are not well understood. Sixteen HIV+youths (15 vertical, 1 transfusion transmissions) receiving combination antiretroviral therapy and 14 age-matched HIV- youths (13-25 years of age) were evaluated with brain two-dimensional (2D) magnetic resonance spectroscopy (MRS) at 3 Tesla (T) and a neuropsychological battery that assessed three cognitive domains (attention/processing speed, psychomotor ability, and executive function). The relationship between brain metabolite ratios and cognitive performance was explored. Compared to HIV- controls, HIV+ subjects had higher sycllo-inositol (Scy)/total creatine (tCr) (+32%, p = 0.016) and higher Scy/total choline (tCho) (+31%, p = 0.018) on 2D-MRS in the right frontal lobe. HIV+ subjects also had higher glutamate (Glu)/tCr (+13%, p = 0.022) and higher Glu/tCho (+15%, p = 0.048) than controls. HIV+ subjects demonstrated poorer attention/processing speed (p = 0.011, d = 1.03) but similar psychomotor and executive function compared to HIV- controls. The attention/processing score also correlated negatively with the ratio of N-acetylaspartate (NAA) to tCr on 2D-MRS (r = -0.75, p = 0.0019) in the HIV- controls, but not in the HIV+ subjects (Fisher's r-z transformation, p < 0.05). Our results suggest that attention/processing speed is impacted by early HIV infection and is associated with right hemisphere NAA/tCr. Scy and Glu ratios are also potential markers of brain health in chronic, lifelong HIV infection in perinatally infected youths receiving antiretroviral therapy.

Protease inhibitors used in the treatment of HIV+ induce beta-cell apoptosis via the mitochondrial pathway and compromise insulin secretion.

Inclusion of HIV protease inhibitors (PIs) in the treatment of people living with HIV+ has markedly decreased mortality but also increased the incidence of metabolic abnormalities, causes of which are not well understood. Here, we report that insulinopenia is exacerbated when Zucker fa/fa rats are exposed to a PI for 7 wk, suggesting that chronic PI exposure adversely affects pancreatic islet beta-cell function. In support of this possibility, we find increased apoptosis, as reflected by TUNEL fluorescence analyses, and reduced insulin-secretory capacity in insulinoma cells and human pancreatic islet cells after in vitro exposures (48-96 h) to clinically relevant PIs (ritonavir, lopinavir, atazanavir, or tipranavir). Furthermore, pancreatic islets isolated from rats administered an HIV-PI for 3 wk exhibit greater cell death than islets isolated from vehicle-administered rats. The higher incidence of HIV-PI-induced cell death was associated with cleavage and, hence, activation of caspase-3 and poly(ADP)-ribose polymerase but not with activation of phospho-pancreatic endoplasmic reticulum (ER) kinase or induction of ER stress apoptotic factor C/EBP homologous protein. Exposure to the HIV-PIs, however, led to activation of mitochondria-associated caspase-9, caused a loss in mitochondrial membrane potential, and promoted the release of cytochrome c, suggesting that HIV-PIs currently in clinically use can induce beta-cell apoptosis by activating the mitochondrial apoptotic pathway. These findings therefore highlight the importance of considering beta-cell viability and function when assessing loss of glycemic control and the course of development of diabetes in HIV+ subjects receiving a protease inhibitor.

Evidence of reduced glutamate in the frontal lobe of HIV-seropositive patients.

Neurological complications associated with the acquired immunodeficiency syndrome, in particular, HIV-associated dementia, continue to plague those infected. We report our finding that the concentration of brain Glu is reduced in the frontal white matter region in this condition. In addition, our data appear to absolve highly active retroviral therapy (HAART) from blame, as drug-naïve patients were equally affected. Our findings suggest that Glu neurotransmission is abnormal and may be a key target for early interventions to reduce the later incidence of neurocognitive impairment and dementia among HIV-seropositive patients.

Glutathione, glutathione peroxidase, and selenium status in HIV-positive and HIV-negative adolescents and young adults.

BACKGROUND: Antioxidant nutrient deficiencies may hasten the progression of HIV disease by impairing antioxidant defenses. OBJECTIVE: The objective of the study was to determine whether HIV infection is associated with poor selenium status and low antioxidant protection by glutathione and glutathione peroxidase (GPX). DESIGN: In a cross-sectional study of 365 HIV-positive and HIV-negative adolescents and young adults, we examined the relation of plasma selenium, whole-blood glutathione, and whole-blood GPX to HIV status, disease severity, immune activation, and oxidative damage. RESULTS: Selenium deficiency (plasma selenium < 0.070 microg/mL) was not seen in any subjects, and plasma selenium in 244 HIV-positive subjects (0.120 +/- 0.0013 microg/mL) did not differ significantly (P = 0.071) from that in 121 HIV-negative subjects (0.125 +/- 0.0020 microg/mL) . However, multiple regression analysis after adjustment for covariates showed a significant (P = 0.002) negative association between HIV-associated immune activation (plasma neopterin) and plasma selenium concentrations. GPX activity was highest in HIV-positive subjects taking antiretroviral therapy (median: 14.2; 25th, 75th percentiles: 11.1, 18.7 U/mL; n = 130), intermediate in HIV-positive subjects not taking antiretroviral therapy (11.8; 9.4, 15.1 U/mL; n = 114), and lowest in HIV-negative subjects (10.6; 8.6, 12.7 U/mL; n = 121; P < 0.05 for all comparisons). GPX was also positively associated with malondialdehyde, a marker of oxidative damage. CONCLUSIONS: Subjects had adequate selenium status, although HIV-related immune activation was associated with lower plasma selenium concentrations. GPX activity appears to have been induced by the oxidative stress associated with HIV infection and use of antiretroviral therapy. Thus, young, well-nourished subjects can mount a compensatory antioxidant response to HIV infection.

Additive effects of HIV and chronic methamphetamine use on brain metabolite abnormalities.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H-MRS) showed decreased neuronal marker N-acetylaspartate and increased glial marker myo-inositol in subjects with chronic methamphetamine use and in subjects infected with HIV. The authors sought to determine whether HIV and a history of chronic methamphetamine use might have additive or interactive effects on brain metabolite abnormalities. METHOD: 1H-MRS was performed in 68 HIV-positive subjects (24 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 2,167 g [SD=2,788] and last use a mean of 4.9 months earlier [SD=6.0]; 44 with no history of drug abuse) and 75 HIV-negative subjects (36 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 8,241 g [SD=16,850] and last use a mean of 6.3 months earlier [SD=7.8]; 39 with no history of drug abuse). Concentrations of N-acetylaspartate, creatine, choline, and myo-inositol were measured in the frontal cortex, frontal white matter, and basal ganglia. RESULTS: HIV-negative subjects with a history of chronic methamphetamine use showed lower concentrations of the neuronal marker N-acetylaspartate in the frontal white matter and basal ganglia and higher concentrations of choline compounds and the glial marker myo-inositol in the frontal cortex, relative to subjects with no history of drug abuse. HIV-positive status was associated with lower concentrations of N-acetylaspartate and creatine in the frontal cortex and higher concentrations of myo-inositol in the white matter, compared with HIV-negative status. Compared to the mean concentrations of metabolites in HIV-negative subjects with no history of drug abuse, the mean concentrations in subjects with HIV and chronic methamphetamine use showed additive effects on N-acetylaspartate in all three regions (-9% in the basal ganglia, -7% in the frontal white matter, and -6% in the frontal gray matter), on creatine in the basal ganglia (-7%), and on myo-inositol in the frontal white matter (+11%). CONCLUSIONS: The combined effects of HIV and chronic methamphetamine use were consistent with an additive model, suggesting additional neuronal injury and glial activation due to the comorbid conditions.

Effect of aging on brain metabolism in antiretroviral-naive HIV patients.

OBJECTIVE: Normal aging as well as HIV infection may lead to inflammatory changes and injury to the brain; however, it is unclear if and how these processes interact. The goal of this pilot study was to evaluate the interaction between aging and HIV infection in the brain using proton magnetic resonance spectroscopy (H-MRS). DESIGN: Analyses of covariance (ANCOVA) were performed to determine the effects of HIV and age, and their interaction, on MRS variables. METHODS: Forty-six HIV patients naive to antiretroviral medications and 58 seronegative control subjects were examined using localized H-MRS in the frontal gray matter, frontal white matter and basal ganglia, and metabolite concentrations were determined. RESULTS: Compared with seronegative controls, HIV-positive subjects showed additional and marked increases in the concentration of glial markers, choline-containing compounds (seronegative controls +2%/decade; HIV-positive subjects +10%/decade) and myoinositol (seronegative controls +3%/decade; HIV-positive subjects +12%/decade), with aging in the frontal white matter. In the basal ganglia, N-acetyl compounds and total creatine decreased with age only in HIV patients (N-acetyl compounds -3.7%/decade; creatine -4%/decade). ANCOVA showed significant interaction effects between HIV and aging on the metabolites in the basal ganglia (N-acetyl peak P = 0.03; creatine P = 0.04) and in the frontal white matter (interaction: choline-containing compounds P = 0.002; myoinositol P = 0.007). CONCLUSION: In the basal ganglia, HIV infection appeared to induce neuronal damage or loss beyond that observed in normal aging. In the frontal white matter, HIV infection seemed to exacerbate glial activation beyond that observed in normal aging.

Associations between dietary antioxidant intake and oxidative stress in HIV-seropositive and HIV-seronegative men and women.

OBJECTIVE: To describe the relationship between dietary antioxidant intake and oxidative stress in clinically stable HIV-positive and HIV-negative adults. DESIGN: A cross-sectional study. METHODS: Average total daily dietary intakes of vitamin C, beta-carotene, alpha-tocopherol, selenium, and zinc from foods and nutritional supplements were estimated in noninstitutionalized individuals using the dietary history method. Plasma malondialdehyde (MDA) concentrations were measured by high-performance-liquid-chromatography (HPLC) whereas peripheral blood mononuclear cell glutathione (PBMC GSH) concentrations were determined spectrophotometrically by an enzymatic recycling assay. Data were analyzed in multiple linear regression models to investigate these relationships. RESULTS: Regression analysis revealed an inverse relationship between selenium intake and plasma MDA in a model that included the five dietary antioxidants ( R 2 = 0.25; p < .02) and with selenium only ( R 2 = 0.19; p < .01). Both models were adjusted for gender, smoking status, and HIV seropositivity. Antioxidant intake was not associated with PBMC GSH ( R 2 = 0.12, p = .36). In univariate analyses, oxidative stress did not significantly differ between clinically stable HIV-positive and healthy HIV-negative study subjects. CONCLUSIONS: This is the first study to characterize the relationship between dietary antioxidant intake from food and supplements with oxidative stress. The results suggested dietary selenium intake was strongly and inversely associated with plasma MDA, but dietary antioxidant intakes were not related to PBMC GSH. This study also provides evidence that HIV infection was not specifically associated with oxidative stress among clinically stable individuals.

In vivo administration of recombinant IL-2 to individuals infected by HIV down-modulates the binding and expression of the transcription factors ying-yang-1 and leader binding protein-1/late simian virus 40 factor.

Leader binding protein-1 (LBP-1)/late SV40 factor (LSF) and ying yang-1 (YY1) transcription factors are involved in the regulation of HIV expression. In particular, YY1 and LBP-1 have been shown to cooperate in repressing HIV-1-long terminal repeat reporter gene expression by in vitro cotransfection experiments. However, no information is available on the levels of expression and activation of these transcription factors in PBMC of HIV-infected individuals. Therefore, we have evaluated the expression and DNA binding activity of YY1 and LBP-1 (LSF) in PBMC of HIV-infected individuals before, during, and after administration of IL-2 in association with antiretroviral therapy (ART), a regimen under consideration for broad clinical use in this disease based on its ability to stably raise the absolute number of circulating CD4+ T lymphocytes. Both YY1- and LBP-1 (LSF)-DNA binding were profoundly down-modulated during administration of IL-2/ART, and a proteolytic activity probably responsible for the reduced expression of the two cellular transcription factors was found activated in PBMC of individuals receiving the immunotherapeutic regimen. This study is the first evidence of modulation of cellular transcription factors following IL-2/ART administration and provides a potential correlate of the transient raises in plasma viremia early reported in patients receiving IL-2 in the absence of ART, thus underscoring the importance of always administering this cytokine to HIV-infected individuals together with potent antiretrovirals.

Dietary micronutrient intake and risk of progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus type 1 (HIV-1)-infected homosexual men.

The authors sought to determine if different levels of dietary intake of micronutrients are associated with the progression of human immunodeficiency virus type 1 (HIV-1) infection to acquired immunodeficiency syndrome (AIDS). A total of 281 HIV-1 seropositive homosexual/bisexual men were seen semiannually since 1984 at the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study. Participants completed a self-administered semiquantitative food frequency questionnaire at baseline. Levels of daily micronutrient intake at baseline were examined in relation to subsequent progression to AIDS (1987 Centers for Disease Control definition; n = 108) during a median follow-up period of 6.8 years. For each nutrient, the authors used a Cox proportional hazards model to adjust for age, presence of symptoms, CD4+ lymphocyte count, energy intake, use of antiretrovirals, and use of Pneumocystis carinii pneumonia prophylaxis. The highest levels of total intake (from food and supplements) of vitamins C and B1 and niacin were associated with a significantly decreased progression rate to AIDS: vitamin C (relative hazard (RH) = 0.55, 95% confidence interval (CI) 0.34-0.91), vitamin B1 (RH = 0.60, 95% CI 0.36-0.98), and niacin (RH = 0.52, 95% CI 0.31-0.86). The relation between total vitamin A intake and progression to AIDS appeared to be U-shaped; the lowest and highest quartiles of intake did most poorly, while the middle two quartiles were associated with significantly slower progression to AIDS (RH = 0.55, 95% CI 0.35-0.88). Increased intake of zinc was monotonically and significantly associated with an increased risk of progression to AIDS (for highest vs. lowest quartiles, RH = 2.06, 95% CI 1.16-3.64). In a final multinutrient model, vitamin A, niacin, and zinc remained significantly associated with progression to AIDS, while vitamin C was only marginally significant.

[Oxidative stress in 29 HIV seropositive patients. Two-year results of a double-blind trial of diethyldithiocarbamate versus placebo]. / Stress oxydatif chez 29 sujets séropositifs. Résultats à 2 ans d'une étude en double insu diéthyldithiocarbamate versus placebo.

Among 29 seropositive subjects who had participated in the HIV 87 therapeutic trial (Mérieux laboratories), the oxidative stress was evaluated at 24 months in 16 treated with diethyldithiocarbamate (dithiocarb) and in 13 who had received the placebo. No significant difference was found between these two groups, whereas the existence of an oxidative stress has been confirmed in seropositive subjects compared with controls.