Methamphetamine Enhances HIV-1 Replication in CD4+ T-Cells via a Novel IL-1β 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-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 immune response. Notably, the effects of Meth abuse on miRNA expression are largely unknown. We studied the effects of Meth on IL-1β and miR-146a, a well-characterized member of the innate immune signaling network. We found that Meth induces miR-146a and triggers an IL-1β 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-1β 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.

Methamphetamine facilitates HIV infection of primary human monocytes through inhibiting cellular viral restriction factors

“…Although METH use has been linked to HIV transmission and infection, its pathological effects on the host cell-mediated specific innate immunity against HIV infection remain to be determined. The earlier studies reported that METH could enhance HIV infection of several cell types, including dendritic cells [ 33 ], macrophages [ 34 , 35 ], CD4 + T cells [ 36 , 37 ], microglia [ 38 ], and neural progenitor cells [ 25 ]. However, it is unclear whether METH facilitates HIV infection of primary human monocytes.…”

Methamphetamine Facilitates HIV Infection of Human Monocytes Through Inhibiting Cellular Viral Restriction Factors

“…Although METH use has been linked to HIV transmission and infection, its pathological effects on the host cell-mediated speci c innate immunity against HIV infection remain to be determined. The earlier studies reported that METH could enhance HIV infection of several cell types, including dendritic cells [31], macrophages [32,33], CD4 + T cells [34,35], and neural progenitor cells [25]. However, it is unclear whether METH facilitates HIV infection of primary human monocytes.…”

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

“…In humans, significantly higher viral loads have been reported in the plasma of HIV-1-infected subjects with a history of METH abuse, as compared with HIV-1-infected individuals not using METH [ 99 ]. METH has been shown to elevate monocyte activation [ 100 ] and enhance HIV-1 replication in monocyte-derived macrophages [ 101 ] and CD4 + T-cells in vitro [ 102 , 103 ], the primary targets for the virus. Since HIV-1 and METH can independently negatively affect BBB integrity and permeability, combined HIV-1 and METH insults may facilitate leukocyte extravasation from blood to brain.…”

“…Recent work indicated that METH-induced downregulation of astrocytic excitatory amino acid transporter-2 (EAAT2), which is responsible for more than 90% of glutamate uptake from the synaptic environment, was exacerbated by interleukin-1β (IL-1β) in primary human astrocytes [133]. IL-1β has been shown to be important for HIV-1 pathobiology [102]. Moreover, EAAT2 was found to be S-nitrosylated in the HAND human brain [46].…”