The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.
"During acute infection, before most individuals know they are infected and/or begin therapy, infection of a greater number of CNS macrophages could increase the amount of HIV in the CNS, accelerating both the spread of infection and the developing neuroinflammation present early after CNS invasion , . This possibility is supported by a recent study showing that methamphetamine is associated with increased neurocognitive impairment in early stage HIV infection . A high percentage of HIV-positive individuals are drug users – and often have poor adherence to medication –. "
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 09/2014; 9(9):e108232. DOI:10.1371/journal.pone.0108232 · 3.23 Impact Factor
"Dysregulation of genes involved in synaptic plasticity, axonal guidance, and interferon response is also a relatively consistent theme. Perhaps the most important conclusions to be drawn from the impressive body of data derived from GWAS, candidate-gene, transcriptomic and epigenetic studies thus far are that: 1) APOE genotype may play a role in older HIV-infected persons [6•, 133•]; 2) genes involved in inflammation and immune regulation in the periphery and CNS, macrophage/monocyte responses to HIV infection, synaptic plasticity, axonal guidance, and mitochondrial function are fundamental in determining neuronal injury and ultimately, neurocognitive function in HIV + individuals; 3) specific gene modules and molecular pathways revealed to be dysregulated in HIV-infection and HAND may now be evaluated for individual variation and therapeutic potential; and 4) dopaminergic dysfunction is altered in HAND and may play a role in HAND pathogenesis among subsets of HIV-infected substance users [91, 134]. Many of these findings still require replication. "
[Show abstract][Hide abstract] ABSTRACT: The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities. Yet, genetic studies still offer a powerful means of advancing individualized care for HIV-infected individuals at risk. There is an urgent need for 1) longitudinal studies using consistent phenotypic definitions of HAND in HIV-infected subpopulations at very high risk of being adversely impacted, such as children, 2) tissue studies that correlate neuropathological changes in multiple brain regions with genomic markers in affected individuals and with changes at the RNA, epigenomic, and/or protein levels, and 3) genetic association studies using more sensitive subphenotypes of HAND. The NIH Brain Initiative and Human Connectome Project, coupled with rapidly evolving systems biology and machine learning approaches for analyzing high-throughput genetic, transcriptomic and epigenetic data, hold promise for identifying actionable biological processes and gene networks that underlie HAND. This review summarizes the current state of understanding of host genetic factors predisposing to HAND in light of past challenges and suggests some priorities for future research to advance the understanding and clinical management of HAND in the cART era.
Current HIV/AIDS Reports 07/2014; 11(3). DOI:10.1007/s11904-014-0222-z · 3.80 Impact Factor
"Methamphetamine is also able to enhance HIV infection of human blood monocytederived macrophages, the primary target site for the virus (Liang et al., 2008) and could facilitate the transport of HIV-infected leukocytes into the brain. This effect could explain the high incidence of AIDS-related neurologic disease in methamphetamine users (Cisneros and Ghorpade, 2012; Weber et al., 2013). The interaction between MDMA and HIV remains to be characterized but there is good evidence showing that ecstasy users may be at a heightened risk for the transmission of HIV and other blood-borne viral infections (BBVI) through risky sexual behaviours (Dunn et al., 2010; Klein et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1β levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA-induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix.
The International Journal of Neuropsychopharmacology 03/2014; 17(08):1-13. DOI:10.1017/S1461145714000145 · 4.01 Impact Factor
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