Methamphetamine Administration Targets Multiple Immune Subsets and Induces Phenotypic Alterations Suggestive of Immunosuppression

Harms, Robert Z.; Morsey, Brenda; Boyer, Craig; Fox, Howard S.; Sarvetnick, Nora

doi:10.1371/journal.pone.0049897

Cited by 59 publications

(76 citation statements)

References 74 publications

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“…Several studies reveal that METH profoundly interferes with immunologic networks and affects diverse leukocyte subsets, thereby increasing susceptibility to infection [6,7,52,53]. However, there has been no systematic approach to dissect out further the role of the primary receptor TAAR1 in METH-induced alterations in immune cell subsets in humans or in animal models.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Sriram

Cenna

Haldar

et al. 2015

Journal of Leukocyte Biology

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The novel transmembrane G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), represents a potential, direct target for drugs of abuse and monoaminergic compounds, including amphetamines. For the first time, our studies have illustrated that there is an induction of TAAR1 mRNA expression in resting T lymphocytes in response to methamphetamine. Methamphetamine treatment for 6 h significantly increased TAAR1 mRNA expression (P < 0.001) and protein expression (P < 0.01) at 24 h. With the use of TAAR1 gene silencing, we demonstrate that methamphetamine-induced cAMP, a classic response to methamphetamine stimulation, is regulated via TAAR1. We also show by TAAR1 knockdown that the down-regulation of IL-2 in T cells by methamphetamine, which we reported earlier, is indeed regulated by TAAR1. Our results also show the presence of TAAR1 in human lymph nodes from HIV-1-infected patients, with or without a history of methamphetamine abuse. TAAR1 expression on lymphocytes was largely in the paracortical lymphoid area of the lymph nodes with enhanced expression in lymph nodes of HIV-1-infected methamphetamine abusers rather than infected-only subjects. In vitro analysis of HIV-1 infection of human PBMCs revealed increased TAAR1 expression in the presence of methamphetamine. In summary, the ability of methamphetamine to activate trace TAAR1 in vitro and to regulate important T cell functions, such as cAMP activation and IL-2 production; the expression of TAAR1 in T lymphocytes in peripheral lymphoid organs, such as lymph nodes; and our in vitro HIV-1 infection model in PBMCs suggests that TAAR1 may play an important role in methamphetamine -mediated immune-modulatory responses.

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Section: Discussionmentioning

confidence: 99%

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Sriram

Cenna

Haldar

et al. 2015

Journal of Leukocyte Biology

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“…Studies have found that morphine suppressed T cell activation in the lymph node, paralleled with a decrease in activation levels of T cells in peripheral blood in nonhuman primates [126]. Methamphetamine has been shown to accelerate the premature demise of activated T cells [127], and reduce the number of dendritic cells and natural killer cells [128,129]. Other than that, excessive reactive oxygen species is produced when astrocytic cells are treated with methamphetamine via CYP2E1, leading to apoptotic cell death [95].…”

Section: Autophagy In Hiv-1 With Co-exposure Of Doamentioning

confidence: 99%

Role of Autophagy in HIV Pathogenesis and Drug Abuse

et al. 2016

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Autophagy is a highly regulated process in which excessive cytoplasmic materials are captured and degraded during deprivation conditions. The unique nature of autophagy that clears invasive microorganisms has made it an important cellular defense mechanism in a variety of clinical situations. In recent years, it has become increasingly clear that autophagy is extensively involved in the pathology of HIV-1. To ensure survival of the virus, HIV-1 viral proteins modulate and utilize autophagy pathway so that biosynthesis of the virus is maximized. At the same time, the abuse of illicit drugs such as methamphetamine, cocaine, morphine, and alcohol is thought to be a significant risk factor for the acquirement and progression of HIV-1. During drug-induced toxicity, autophagic activity has been proved to be altered in various cell types. Here we review the current literature on the interaction between autophagy, HIV-1, and drug abuse, and discuss the complex role of autophagy during HIV-1 pathogenesis in co-exposure to illicit drugs.

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“…Therefore, METH use has been shown to alter or suppress functions of immune cells that are implicated in HIV-1 pathogenesis. For example, METH is known to regulate T cell function including proliferation, cytokine production and T cell-mediated immune response [52,53]. In addition, METH is demonstrated to downregulate the expression of anti-viral cytokine IFN-α in macrophages and dendritic cells [45,54].…”

Section: Immunomodulatory Functions Of Meth May Modulate Hiv-1 Infectmentioning

confidence: 99%

The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis

Passaro

Pandhare

Qian

et al. 2015

J Neuroimmune Pharmacol

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The global HIV/AIDS pandemic has claimed the lives of an estimated 35 million people. A significant barrier for combating this global pandemic is substance use since it is associated with HIV transmission, delayed diagnosis/initiation of therapy, and poor adherence to therapy. Clinical studies also suggest a link between substance use and HIV-disease progression/AIDS-associated mortality. Methamphetamine (METH) use is one of the fastest-growing substance use problems in the world. METH use enhances high-risk sexual behaviors, therefore increases the likelihood of HIV-1 acquisition. METH use is also associated with higher viral loads, immune dysfunction, and antiretroviral resistance. Moreover, METH use has also been correlated with rapid progression to AIDS. However, direct effects of METH on HIV-1 disease progression remains poorly understood because use of METH and other illicit drugs is often associated with reduced/non adherence to ART. Nevertheless, in vitro studies demonstrate that METH increases HIV-1 replication in cell cultures and animal models. Thus, it has been proposed that METH’s potentiating effects on HIV-1 replication may in part contribute to the worsening of HIV-1 pathogenesis. However, our recent data demonstrate that METH inhibits HIV-1 replication in CD4+ T cells and challenges this paradigm. Thus, the goal of this review is to systematically examine the published literature to better understand the complex interaction between METH abuse and HIV-1 disease progression.

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Methamphetamine Administration Targets Multiple Immune Subsets and Induces Phenotypic Alterations Suggestive of Immunosuppression

Cited by 59 publications

References 74 publications

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Role of Autophagy in HIV Pathogenesis and Drug Abuse

The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis

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