Methamphetamine increases HIV infectivity in neural progenitor cells

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 and 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.

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

“…In our experiments, exposure to HIV-ECVs increased NeuN positive cell number. These results are in line with the literature reports demonstrating that NPCs could be infected with HIV (73)(74)(75) and HIV affected their proliferation and survival in vitro and in vivo (73,76).…”

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

“…In our experiments, exposure to HIV-ECVs increased NeuN positive cell number. These results are in line with the literature reports demonstrating that NPCs could be infected with HIV [73][74][75] and HIV affected their proliferation and survival in vitro and in vivo [73,76]. Moreover, the number of hippocampal NPCs in postmortem brains in HIV patients with dementia was lower when compared to patients without dementia [26].…”

Methamphetamine functions as a novel CD4+ T-cell activator via the sigma-1 receptor to enhance HIV-1 infection

“…Previous studies in in vitro models have demonstrated that Meth enhances HIV-1 replication in T-cells, DCs, macrophages and neural progenitor cells 11–14 . The significance of these results is supported by an epidemiological study, which demonstrated increased viral loads in Meth using HIV-1 infected individuals compared with non-users who were infected 28 .…”

“…Further, Meth has been shown to enhance HIV-1 infection in dendritic cells (DCs) and macrophages by regulating the expression of HIV-1 co-receptors and DC-SIGN 12,13 . In microglial cells, Meth enhanced HIV-1 transcription via NFκB/SP1 dependent activation of HIV-1 LTR 14 . Conversely, Mantri et al .…”