Internalization of Modified Lipids by CD36 and SR-A Leads to Hepatic Inflammation and Lysosomal Cholesterol Storage in Kupffer Cells

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH

Neurocognitive Consequences of HIV Infection in Older Adults: An Evaluation of the “Cortical” Hypothesis

The incidence and prevalence of older adults living with HIV infection is increasing. Recent reports of increased neuropathologic and metabolic alterations in older HIV+ samples, including increased cortical beta-amyloid, have led some researchers to suggest that aging with HIV may produce a neuropsychological profile akin to that which is observed in “cortical” dementias (e.g., impairment in memory consolidation). To evaluate this possibility, we examined four groups classified by HIV serostatus and age (i.e., younger ≤40 years and older ≥50 years): (1) Younger HIV− (n = 24); (2) Younger HIV+ (n = 24); (3) Older HIV− (n = 20); and (4) Older HIV+ (n = 48). Main effects of aging were observed on episodic learning and memory, executive functions, and visuoconstruction, and main effects of HIV were observed on measures of verbal learning and memory. The interaction of age and HIV was observed on a measure of verbal recognition memory, which post hoc analyses showed to be exclusively attributed to the superior performance of the younger HIV seronegative group. Thus, in this sample of older HIV-infected individuals, the combined effects of HIV and aging do not appear to result in a “cortical” pattern of cognitive deficits

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

Impact of HIV and aging on neuropsychological function

Cognitive efficiency decreases with age, and advancing age is the leading risk factor for most neurodegenerative disorders that result in dementia. In HIV infection, risk for cognitive impairment is consistently linked to advancing chronological age. As the HIV epidemic enters its fourth decade in the USA, extended life expectancy will likely result in an increased prevalence of cognitive disorders by virtue of these factors. However, it is less clear if HIV potentiates or accelerates the risk for cognitive impairment given that most reports are mixed or demonstrate only a small interaction effect. More critically, it is unclear if HIV will modulate the neuropathology associated with non-HIV cognitive disorders in a manner that will increase risk for diseases such as cerebrovascular and Alzheimer’s disease. In the coming years, with increasing numbers of HIV+ patients entering their 60s and 70s, background risk for neurodegenerative disorders will be sufficiently high as to inform this issue on clinical grounds. This review summarizes knowledge of cognition in HIV as it relates to age and presents some emerging controversies

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