Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers

Serum angiopoietin-2 and soluble VEGF receptor 2 are surrogate markers for plasma leakage in patients with acute dengue virus infection

Background: Endothelial cell dysfunction is believed to play an important role in the pathogenesis of plasma leakage in patients with acute dengue virus (DENV) infection. Several factors, produced by activated endothelial cells, have been associated with plasma leakage or severe disease in patients with infectious diseases. Objectives: The aim of this study was to investigate which of these markers could serve as a surrogate marker for the occurrence of plasma leakage in patients with acute DENV infection. Study design: A case-control study was performed in patients with acute DENV infection in Santos, Brazil. Plasma leakage was detected with X-ray and/or ultrasound examination at admission. Serum levels of soluble endoglin, endothelin-1, angiopoietin-2, VEGF, soluble VEGFR-2, MMP-2, MMP-9, TIMP-1 and TIMP2 were determined using commercially available ELISAs. Results: Increased levels of angiopoietin-2, endothelin-1 and MMP-2 and decreased levels of soluble VEGFR2 were significantly associated with the occurrence of plasma leakage. An unsupervised cluster analysis confirmed that angiopoietin-2 and soluble VEGFR-2 were strongly associated with clinical apparent vascular leakage. Conclusion: Angiopoietin-2 and soluble VEGFR-2 can serve as surrogate markers for the occurrence of plasma leakage in patients with acute DENV infection. (C) 2014 Elsevier B.V. All rights reserved

Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease

Background: Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection. Methods: Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of Sao Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) clus Results: Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease. Conclusions: The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis

Symptoms of common mental disorder and cognitive associations with seropositivity among a cohort of people coming for testing for HIV/AIDS in Goa, India: a cross-sectional survey.

BACKGROUND: The majority of research on HIV/AIDS and mental health has been carried out among clinical populations: the time of onset of comorbid depression and the mechanisms for this are therefore unclear. Although there is evidence to suggest that asymptomatic people living with HIV/AIDS exhibit some cognitive deficits, the prevalence of poor cognitive functioning among people in low income settings at an early, pre-clinical stage has not yet been investigated. METHODS: We used a cross-sectional survey design to test the hypotheses that symptoms of Common Mental Disorder (CMD) and low scores on cognitive tests would be associated with seropositivity among participants coming for testing for HIV/AIDS. Participants were recruited at the time of coming for testing for HIV/AIDS; voluntary informed consent was sought for participation in research interviews and data linkage with HIV test results. Baseline questionnaires including sociodemographic variables and measures of mental health (PHQ-9, GAD-7, panic disorder questions, AUDIT and delayed word list learning and recall and animal naming test of verbal fluency) were administered by trained interviews. HIV status data was extracted from clinical records. RESULTS: CMD and scoring below the educational norm on the test of verbal fluency were associated with testing positive for HIV/AIDS in bivariate analysis (OR = 2.26, 1.31-3.93; OR = 1.77, 1.26-2.48, respectively). After controlling for the effects of confounders, the association between CMD and seropositivity was no longer statistically significant (AOR = 1.56, 0.86-2.85). After adjusting for the effects of confounders, the association between low scores on the test of verbal fluency and seropositivity was retained (AOR = 1.77, 1.27-2.48). CONCLUSIONS: Our findings provide tentative evidence to suggest that low cognitive test scores (and possibly depressive symptoms) may be associated with HIV status among people who have yet to receive their HIV test results. Impaired cognitive functioning and depression-like symptoms may be the result of the same underlying neurological damage. CMD and cognitive impairment may overlap to a greater extent than previously assumed. If replicated, this may have implications for the way in which we measure and treat CMD and cognitive functioning among people living with HIV/AIDS

Labor force participation and health-related quality of life in HIV-positive men who have sex with men: The multicenter AIDS cohort study

Too many people with HIV have left the job market permanently and those with reduced work capacity have been unable to keep their jobs. There is a need to examine the health effects of labor force participation in people with HIV. This study presents longitudinal data from 1,415 HIV-positive men who have sex with men taking part in the Multicenter AIDS Cohort Study. Generalized Estimating Equations show that employment is associated with better physical and mental health quality of life and suggests that there may be an adaptation process to the experience of unemployment. Post hoc analyses also suggest that people who are more physically vulnerable may undergo steeper health declines due to job loss than those who are generally healthier. However, this may also be the result of a selection effect whereby poor physical health contributes to unemployment. Policies that promote labor force participation may not only increase employment rates but also improve the health of people living with HIV. © Springer Science+Business Media, LLC 2012