Abstract

HIV-1 infection and methamphetamine (METH) abuse frequently occur simultaneously and may have synergistic pathological effects. Although HIV-positive/active METH users have been shown to have higher HIV viral loads and experience more severe neurological complications than non-users, the direct impact of METH on HIV infection and its link to the development of neurocognitive alternations are still poorly understood. In the present study, we hypothesized that METH impacts HIV infection of neural progenitor cells (NPCs) by a mechanism encompassing NFκB/SP1-mediated HIV LTR activation. Mouse and human NPCs were infected with EcoHIV (modified HIV virus infectious to mice) and HIV, respectively, in the presence or absence of METH (50 or 100 μm). Pretreatment with METH, but not simultaneous exposure, significantly increased HIV production in both mouse and human NPCs. To determine the mechanisms underlying these effects, cells were transfected with different variants of HIV LTR promoters and then exposed to METH. METH treatment induced transcriptional activity of the HIV LTR promotor, an effect that required both NFκB and SP1 signaling. Pretreatment with METH also decreased neuronal differentiation of HIV-infected NPCs in both in vitro and in vivo settings. Importantly, NPC-derived daughter cells appeared to be latently infected with HIV. This study indicates that METH increases HIV infectivity of NPCs, through the NFκB/SP1-dependent activation of the HIV LTR and with the subsequent alterations of NPC neurogenesis. Such events may underlie METH- exacerbated neurocognitive dysfunction in HIV-infected patients.

Highlights

  • HIV-1 infection and methamphetamine (METH) abuse frequently occur simultaneously and may have synergistic pathological effects

  • This study indicates that METH increases HIV infectivity of neural progenitor cells (NPCs), through the NF␬B/SP1-dependent activation of the HIV LTR and with the subsequent alterations of NPC neurogenesis

  • Mouse or human NPCs were treated with METH simultaneously or 24 h before HIV infection. mNPCs were infected with EcoHIV (Fig. 1, A and B), whereas hNPCs were infected with HIV (Fig. 1, C and D)

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Summary

Introduction

HIV-1 infection and methamphetamine (METH) abuse frequently occur simultaneously and may have synergistic pathological effects. We hypothesized that METH impacts HIV infection of neural progenitor cells (NPCs) by a mechanism encompassing NF␬B/SP1-mediated HIV LTR activation. This study indicates that METH increases HIV infectivity of NPCs, through the NF␬B/SP1-dependent activation of the HIV LTR and with the subsequent alterations of NPC neurogenesis. METH abuse creates social problems and has devastating effects on health, generating costs of approximately $24 million/year in the United States [75], but it has been shown to contribute to increased transmission of infectious diseases, including HIV [1,2,3,4]. METH abuse itself is linked to alterations in brain structure and dopaminergic parameters, as well as decline of cognitive function [7] When comorbidity of both HIV and METH occurs, additive deleterious effects on neuropsychological functions can be observed.

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