Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells

Department of Immunology, College of Medicine, Florida International University, Miami, FL 33155, USA.
Journal of Neuroimmune Pharmacology (Impact Factor: 4.11). 11/2008; 4(1):129-39. DOI: 10.1007/s11481-008-9128-0
Source: PubMed


The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.

1 Follower
10 Reads
  • Source
    • "For all the in vitro studies , leukopacks were commercially obtained from the community blood bank ( One Blood , Miami , FL , USA ) from at least three different blood donors . MDDC were prepared from peripheral blood mononuclear cells ( PBMC ) as previously described by us ( Nair et al . , 2005 , 2009 ; Agudelo et al . , 2013 ) . Briefly , after the separation of adherent and non - adherent cells , monocyte were further purified using the EasySep TM Human Monocyte Enrichment Kit ( Stemcell Technologies , catalog #19059 ) , and allowed to differentiate into MDDC by culturing them with complete RPMI media containing 100 U / ml of GM - "
    [Show abstract] [Hide abstract]
    ABSTRACT: During human immunodeficiency virus (HIV) infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC). However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%), THC (5 and 10 μM), or JWH-015 (5 and 10 μM) for 4–7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR) estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV + EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV + JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV + THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection.
    Full-text · Article · Dec 2015 · Frontiers in Microbiology
  • Source
    • "Moreover, in HIV infected meth abusers, a more cognitive impairment was related to a smaller hippocampal volume (Berman et al., 2008). The expression of HIV co-receptors, CXCR4 and CCR5, and HIV replication in astrocytes were both increased in presence of meth (Nair et al., 2009). BBB dysfunction and an increase in the expression of pro-inflammatory cytokinesis were observed, which can lead to meth-neurotoxicity (Czub et al., 2001; Nath et al., 2002). "

    Full-text · Article · Mar 2015 · Frontiers in Microbiology
  • Source
    • "HIV infection is highly regulated by the expression of the HIV entry co-receptors CXCR4 and CCR5. METH-treated groups demonstrated that both of these receptors exhibited up-regulated expression after METH treatment on dendritic cells, signifying increased susceptibility to HIV infection (Liang et al., 2008; Nair et al., 2009; Nair and Saiyed, 2011). In addition, METH exposure significantly reduced expression of ERK2 and up-regulated p32 MAPK genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of methamphetamine (METH) use is estimated at ~35 million people worldwide, with over 10 million users in the United States. METH use elicits a myriad of social consequences and the behavioral impact of the drug is well understood. However, new information has recently emerged detailing the devastating effects of METH on host immunity, increasing the acquisition of diverse pathogens and exacerbating the severity of disease. These outcomes manifest as modifications in protective physical and chemical defenses, pro-inflammatory responses, and the induction of oxidative stress pathways. Through these processes, significant neurotoxicities arise, and, as such, chronic abusers with these conditions are at a higher risk for heightened consequences. METH use also influences the adaptive immune response, permitting the unrestrained development of opportunistic diseases. In this review, we discuss recent literature addressing the impact of METH on infection and immunity, and identify areas ripe for future investigation.
    Full-text · Article · Jan 2014 · Frontiers in Neuroscience
Show more