Dataset Information

Methamphetamine Enhances HIV-1 Replication in CD4+ T-Cells via a Novel IL-1? Auto-Regulatory Loop.

ABSTRACT: Methamphetamine (Meth) abuse is a worldwide public health problem and contributes to HIV-1 pathobiology and poor adherence to anti-retroviral therapies. Specifically, Meth is posited to alter molecular mechanisms to provide a more conducive environment for HIV-1 replication and spread. Enhanced expression of inflammatory cytokines, such as Interleukin-1? (IL-1?), has been shown to be important for HIV-1 pathobiology. In addition, microRNAs (miRNAs) play integral roles in fine-tuning the innate immune response. Notably, the effects of Meth abuse on miRNA expression are largely unknown. We studied the effects of Meth on IL-1? and miR-146a, a well-characterized member of the innate immune signaling network. We found that Meth induces miR-146a and triggers an IL-1? auto-regulatory loop to modulate innate immune signaling in CD4+ T-cells. We also found that Meth enhances HIV-1 replication via IL-1 signaling. Our results indicate that Meth activates an IL-1? feedback loop to alter innate immune pathways and favor HIV-1 replication. These observations offer a framework for designing targeted therapies in HIV-infected, Meth using hosts.

SUBMITTER: Lawson KS

PROVIDER: S-EPMC7025468 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Methamphetamine Enhances HIV-1 Replication in CD4<sup>+</sup> T-Cells via a Novel IL-1β Auto-Regulatory Loop.

Lawson Kaycie S KS Prasad Anil A Groopman Jerome E JE

Frontiers in immunology 20200207

Methamphetamine (Meth) abuse is a worldwide public health problem and contributes to HIV-1 pathobiology and poor adherence to anti-retroviral therapies. Specifically, Meth is posited to alter molecular mechanisms to provide a more conducive environment for HIV-1 replication and spread. Enhanced expression of inflammatory cytokines, such as Interleukin-1β (IL-1β), has been shown to be important for HIV-1 pathobiology. In addition, microRNAs (miRNAs) play integral roles in fine-tuning the innate i ...[more]

PMID: 32117283

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Project description:CCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4(+)Foxp3(+) regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4(+)Foxp3(+) Treg homing has not been investigated.Infected wild-type (Ccr5(+/+)) and CCR5-deficient (Ccr5(-/-)) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs was used to evaluate the role of Tregs in JE progression.CCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Compared to Ccr5(+/+) mice, Ccr5(-/-) mice unexpectedly showed increased responses of IFN-?(+)NK and CD8(+) T cells in the spleen, but not CD4(+) T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17(+)CD4(+) Th17 cells and correspondingly reduced CD4(+)Foxp3(+) Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17(+)CD4(+) Th17 cells, myeloid-derived Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Instead, adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-?) in the spleen and brain, and transferred CCR5(+) Tregs were found to produce IL-10.CCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4(+)Foxp3(+) Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.

Dataset Information

Methamphetamine Enhances HIV-1 Replication in CD4+ T-Cells via a Novel IL-1? Auto-Regulatory Loop.

Publications

Methamphetamine Enhances HIV-1 Replication in CD4<sup>+</sup> T-Cells via a Novel IL-1β Auto-Regulatory Loop.

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