Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission

Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG)-standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.     

Drugs of Abuse,Dopamine, and HIV-Associated Neurocognitive Disorders/HIV-Associated Dementia

Although the incidence of HIV-associated dementia (HAD) has declined, HIV-associated neurocognitive disorders (HAND) remain a significant health problem despite use of highly active antiretroviral therapy. In addition, the incidence and/or severity of HAND/HAD are increased with concomitant use of drugs of abuse, such as cocaine, marijuana, and methamphetamine. Furthermore, exposure to most drugs of abuse increases brain levels of dopamine, which has been implicated in the pathogenesis of HIV. This review evaluates the potential role of dopamine in the potentiation of HAND/HAD by drugs of abuse. In the brain, multiplication of HIV in infected macrophages/microglia could result in the release of HIV proteins such as gp120 and Tat, which can bind to and impair dopamine transporter (DAT) functions, leading to elevated levels of dopamine in the dopaminergic synapses in the early asymptomatic stage of HIV infection. Exposure of HIV-infected patients to drugs of abuse, especially cocaine and methamphetamine, can further increase synaptic levels of dopamine via binding to and subsequently impairing the function of DAT. This accumulated synaptic dopamine can diffuse out and activate adjacent microglia through binding to dopamine receptors. The activation of microglia may result in increased HIV replication as well as increased production of inflammatory mediators such as tumor necrosis factor (TNF)-alpha and chemokines. Increased HIV replication can lead to increased brain viral load and increased shedding of HIV proteins, gp120 and Tat. These proteins, as well as TNF-alpha, can induce cell death of adjacent dopaminergic neurons via apoptosis. Autoxidation and metabolism of accumulated synaptic dopamine can lead to generation of reactive oxygen species (hydrogen peroxide), quinones, and semiquinones, which can also induce apoptosis of neurons. Increased cell death of dopaminergic neurons can eventually lead to dopamine deficit that may exacerbate the severity and/or accelerate the progression of HAND/HAD.     

HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

The human immunodeficiency virus-1 (HIV-1) regulatory protein Tat plays an important role during HIV-1-associated neurocognitive disorders (HAND) by inducing neuronal autophagy. In this study, we used immunohistochemistry, immunofluorescence, western blot, qRT-PCR, and RNA interference to elucidate the involvement of Bcl-2-associated athanogene 3 (BAG3) in the pathogenesis of HIV-1 Tat-induced autophagy during HAND. We found that BAG3 expression is elevated in astrocytes in frontal cortex of macaques infected with simian immunodeficiency virus-human immunodeficiency chimeric virus (SHIV). In addition, in human primary glioblastoma cells (U87), HIV-1 Tat upregulated BAG3 in an NF-κB-dependent manner to induce autophagy. Importantly, suppression of BAG3 or inhibition of NF-κB activity reversed the HIV-1 Tat-induced autophagy. These results indicate that HIV-1 Tat induces autophagy by upregulating BAG3 via NF-κB signaling, which suggests BAG3 and NF-κB could potentially serve as novel targets for HAND therapies.     

Methamphetamine induces thoracic aortic aneurysm/dissection through C/EBPβ

AimsThoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism.Methods and resultsA new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor β-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein β (C/EBPβ) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPβ binding to MMP2 and MMP9 promoters. Blocking C/EBPβ significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPβ-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPβ, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease.ConclusionsOur study demonstrated that METH exposure has a casual effect on TAAD. C/EBPβ mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPβ may be a potential factor for TAAD clinical diagnosis or treatment.     

Nicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation

Infection with the human immunodeficiency virus (HIV) remains a threat to global health. Since its discovery, many efforts have been directed at understanding the mechanisms and consequences of infection. Although there have been substantial advances since the advent of antiretroviral therapy, there are still complications that significantly compromise the health of infected patients, particularly, chronic inflammation and HIV-associated neurocognitive disorders (HAND). In this review, a new perspective is addressed in the field of HIV, where the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is the protagonist. We comprehensively discuss the available evidence implicating α7-nAChRs in the context of HIV and provide possible explanations about its role in HAND and inflammation in both the central nervous system and the periphery.     

Exosome-mediated shuttling of microRNA-29 regulates HIV Tat and morphine-mediated Neuronal dysfunction

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3′-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.     

Mechanisms of the Blood–Brain Barrier Disruption in HIV-1 Infection

Summary 1. Alterations of brain microvasculature and the disruption of the blood–brain barrier (BBB) integrity are commonly associated with human immunodeficiency virus type 1 (HIV-1) infection. These changes are most frequently found in human immunodeficiency virus-related encephalitis (HIVE) and in human immunodeficiency virus-associated dementia (HAD).2. It has been hypothesized that the disruption of the BBB occurs early in the course of HIV-1 infection and can be responsible for HIV-1 entry into the CNS.3. The current review discusses the mechanisms of injury to brain endothelial cells and alterations of the BBB integrity in HIV-infection with focus on the vascular effects of HIV Tat protein. In addition, this review describes the mechanisms of the BBB disruption due to HIV-1 or Tat protein interaction with selected risk factors for HIV infection, such as substance abuse and aging.This revised article was published online in May 2005 with a February 2005 cover date.     

Macrophages, chemokines and neuronal injury in HIV-1-associated dementia.

Human immunodeficiency virus type-one (HIV- 1)-associated dementia (HAD) is manifested as a spectrum of behavioral, motor and cognitive dysfunctions. The disorder commonly occurs during late stage HIV disease and remains an important complication despite highly active antiretroviral therapies. A metabolic encephalopathy, fueled by neurotoxic secretions from brain mononuclear phagocytes (MP) (macrophages and microglia) underlies HIV- I neuropathogenesis. One pivotal question, however, is how brain MP evolve from neurotrophic to neurotoxic cells. The interplay between the virus, the macrophage and the neuron has just recently begun to be unraveled. Along with a multitude of other MP secretory products, chemokines effect neuronal function by engaging neuronal receptors then activating pathways that alter synaptic transmission, cell growth, injury and protection. Both neurons and glia secrete chemokines. Interestingly, HIV-1 and its gene products can mimic chemokine neuronal signaling by binding to neuronal chemokine receptors or by other non-specific mechanisms. The elucidation of mechanisms involved in chemokine-mediated neural compromise will likely provide unique insights into the pathogenesis and treatment, not only of HAD, but of a wide range of neurodegenerative disorders.     

HIV infection is associated with increased NTPDase activity that correlates with CD39-positive lymphocytes

Infection with the human immunodeficiency virus (HIV) results in alterations in immune cells such as an increase or decrease of cytokine secretion and immunodeficiency. HIV causes a state of chronic cellular activation that can induce apoptosis in lymphocyte T-helpers, making the patient susceptive to opportunistic infections. The biochemical mechanisms involved in this immune response to HIV have been researched. Here, we have shown for the first time that ATP and ADP hydrolysis are essential for the immune response to HIV. Our results clearly indicate an increase of NTPDase-1 (EC 3.6.1.5) activity in lymphocytes of HIV-positive patients, confirmed by an enhanced CD39 expression on its surface. These results suggest that NTPDase-1 may be important to keep an adequate balance between the generation and consumption of ATP and to preserve cellular integrity and immune response to the HIV infection.     

Epigenetic Alterations in the Brain Associated with HIV-1 Infection and Methamphetamine Dependence

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.     

Increased in vivo activation of microglia and astrocytes in the brains of mice transgenic for an infectious R5 human immunodeficiency virus type 1 provirus and for CD4-specific expression of human cyclin T1 in response to stimulation by lipopolysaccharides

Inflammatory mediators and viral products produced by human immunodeficiency virus (HIV)-infected microglia and astrocytes perturb the function and viability of adjacent uninfected neuronal and glial cells and contribute to the pathogenesis of HIV-associated neurocognitive disorders (HAND). In vivo exposure to lipopolysaccharide (LPS) activates parenchymal microglia and astrocytes and induces cytokine and chemokine production in the brain. HIV-infected individuals display increased circulating LPS levels due to microbial translocation across a compromised mucosa barrier. We hypothesized that HIV-infected microglia and astrocytes display increased sensitivity to the proinflammatory effects of LPS, and this combines with the increased levels of systemic LPS in HIV-infected individuals to contribute to the development of HAND. To examine this possibility, we determined the in vivo responsiveness of HIV-infected microglia and astrocytes to LPS using our mouse model, JR-CSF/human cyclin T1 (JR-CSF/hu-cycT1) mice, which are transgenic for both an integrated full-length infectious HIV type 1 (HIV-1) provirus derived from the primary R5-tropic clinical isolate HIV-1(JR-CSF) regulated by the endogenous HIV-1 long terminal repeat and the hu-cycT1 gene under the control of a CD4 promoter. In the current report, we demonstrated that in vivo-administered LPS more potently activated JR-CSF/hu-cycT1 mouse microglia and astrocytes and induced a significantly higher degree of monocyte chemoattractant protein production by JR-CSF/hu-cycT1 astrocytes compared to that of the in vivo LPS response of control littermate mouse microglia and astrocytes. These results indicate that HIV infection increases the sensitivity of microglia and astrocytes to inflammatory stimulation and support the use of these mice as a model to investigate various aspects of the in vivo mechanism of HIV-induced neuronal dysfunction.     

Human Synaptic Plasticity Gene Expression Profile and Dendritic Spine Density Changes in HIV-Infected Human CNS Cells: Role in HIV-Associated Neurocognitive Disorders (HAND)

HIV-associated neurocognitive disorders (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occur in approximately 50% of HIV infected individuals. Our current understanding of HAND emanates mainly from HIV-1 subtype B (clade B), which is prevalent in USA and Western countries. However very little information is available on neuropathogenesis of HIV-1 subtype C (clade C) that exists in Sub-Saharan Africa and Asia. Therefore, studies to identify specific neuropathogenic mechanisms associated with HAND are worth pursuing to dissect the mechanisms underlying this modulation and to prevent HAND particularly in clade B infection. In this study, we have investigated 84 key human synaptic plasticity genes differential expression profile in clade B and clade C infected primary human astrocytes by using RT² Profile PCR Array human Synaptic Plasticity kit. Among these, 31 and 21 synaptic genes were significantly (≥3 fold) down-regulated and 5 genes were significantly (≥3 fold) up-regulated in clade B and clade C infected cells, respectively compared to the uninfected control astrocytes. In flow-cytometry analysis, down-regulation of postsynaptic density and dendrite spine morphology regulatory proteins (ARC, NMDAR1 and GRM1) was confirmed in both clade B and C infected primary human astrocytes and SK-N-MC neuroblastoma cells. Further, spine density and dendrite morphology changes by confocal microscopic analysis indicates significantly decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC neuroblastoma cells compared to uninfected and clade C infected cells. We have also observed that, in clade B infected astrocytes, induction of apoptosis was significantly higher than in the clade C infected astrocytes. In conclusion, this study suggests that down-regulation of synaptic plasticity genes, decreased dendritic spine density and induction of apoptosis in astrocytes may contribute to the severe neuropathogenesis in clade B infection.     

Drug abuse,psychiatric disorders,and AIDS. Dual and triple diagnosis.

Substance abuse and psychiatric disorders commonly occur together. This form of dual diagnosis is notable because it complicates assessment and makes treatment more difficult for both psychiatric and drug abuse problems. Drugs can cause psychiatric disorders and can also be used as an attempt to "cure" them by self-medication. The spread of the human immunodeficiency virus (HIV) among drug users has added a third potential clinical problem, that of the acquired immunodeficiency syndrome, to the difficulties already presented by drug abuse and psychiatric disorders. Patients with this triple diagnosis pose challenges to primary care physicians as well as addiction medicine specialists or psychiatrists. Assessment should include a drug abuse history, preferably corroborated by others, evaluation of the mental state, and examination focusing on signs of drug abuse and HIV infection. Treatment should include the management of HIV disease, abstinence from drug abuse, and access to psychiatric care. New systems of health care service, including interdisciplinary case management, may be needed to manage patients with a triple diagnosis.     

Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis

It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection.     

精液源性病毒感染增强因子SEVI-HIV性传播中的重要因素

精液源性病毒增强因子(Semen-derived enhancer of viral infection,SEVI)是前列腺酸性磷酸酶(Prostatic acidphosphatase,PAP)位于PAP248-286的多肽片段,可增强人免疫缺陷病毒(Human immunodeficiency virus,HIV)的感染性。SEVI促进HIV感染的作用机制包括:①富含阳离子氨基酸残基的SEVI能通过静电作用降低HIV病毒颗粒与靶细胞之间的静电排斥;②SEVI在人体液中呈无序状态,利于病毒与靶细胞膜相互作用;③SEVI直接捕获HIV颗粒,提高病毒在靶细胞表面沉降速度,促进病毒与靶细胞的吸附和融合。目前已发现能抑制SEVI活性的物质包括:绿茶来源的EGCG(没食子儿茶素没食子酸酯)、氨基喹啉类小分子化合物Surfen、ThT类似物BTA-EG6等,能通过阻断HIV与SEVI结合或阻止其淀粉样纤维的形成,降低SEVI的病毒感染增强作用。研究SEVI的生物学特性及作用机制对防治HIV感染具有较为重要的指导意义。     

Methamphetamine induces autophagy as a pro-survival response against apoptotic endothelial cell death through the Kappa opioid receptor

Methamphetamine (METH) is a psychostimulant with high abuse potential and severe neurotoxicity. Recent studies in animal models have indicated that METH can impair the blood–brain barrier (BBB), suggesting that some of the neurotoxic effects resulting from METH abuse could be due to barrier disruption. We report here that while chronic exposure to METH disrupts barrier function of primary human brain microvascular endothelial cells (HBMECs) and human umbilical vein endothelial cells (HUVECs), an early pro-survival response is observed following acute exposure by induction of autophagic mechanisms. Acute METH exposure induces an early increase in Beclin1 and LC3 recruitment. This is mediated through inactivation of the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K pathway, and upregulation of the ERK1/2. Blockade of Kappa opioid receptor (KOR), and treatment with autophagic inhibitors accelerated METH-induced apoptosis, suggesting that the early autophagic response is a survival mechanism for endothelial cells and is mediated through the kappa opioid receptor. Our studies indicate that kappa opioid receptor can be therapeutically exploited for attenuating METH-induced BBB dysfunction.     

Cytocidal effect of tumor necrosis factor on cells chronically infected with human immunodeficiency virus (HIV): enhancement of HIV replication.

Tumor necrosis factor (TNF), a monokine initially described as a tumoricidal agent, facilitated the replication of human immunodeficiency virus (HIV) in vitro. The viability of human T-cell line MOLT-4/HIV, chronically infected with HIV, was affected by the addition of a low dose (10 ng/ml) of recombinant TNF-alpha (rTNF-alpha), while uninfected MOLT-4 cells were resistant to treatment with rTNF-alpha at concentrations up to 1,000 ng/ml. A marked increase in the level of HIV-specific RNA was detected in MOLT-4/HIV cells as early as 1 h after exposure to rTNF-alpha and reached almost maximum level within 6 h. Production of HIV particles from MOLT-4/HIV was also increased at 6 h after treatment with rTNF-alpha. Nearly identical phenomena were observed in CCRF-CEM/HIV, Jurkat/HIV, and H9/HIV cells, although the sensitivity of these cell lines to rTNF-alpha varied. A human T-lymphotropic virus type 1-infected cell line, MT-4, was insensitive to treatment with rTNF-alpha.