We have previously shown in infant rats that brief and repeated experiences with a stressed dam outside the homecage (maltreatment) alters methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) gene within the developing and adult prefrontal cortex. BDNF is a key mediator of activity-dependent processes that have a profound influence on neural development and plasticity. Here we examined whether maltreatment also alters bdnf DNA methylation in two additional regions known to be prominently affected by diverse forms of early-life adversity in humans, the hippocampus and amygdala. We found significant bdnf DNA methylation modifications present within the adult hippocampus (dorsal and ventral) and amygdala (central/basolateral complex). We observed that the nature of change differed between sexes, gene locus (bdnf I vs. IV), and brain region. Furthermore, a manipulation that did not produce any obvious behavior difference in infants (brief and repeated experiences with a nurturing foster dam) also had long-term effects on methylation. These data provide further empirical support of DNA methylation modifications as biological consequences of caregiving environments.

The human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) protein functions both intracellularly and extracellularly. Intracellularly, the main function is to enhance transcription of the viral promoter. However, this process only requires a small amount of intracellular Tat. The majority of Tat is secreted through an unconventional mechanism by binding to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P ), a phospholipid in the inner leaflet of the plasma membrane that is required for secretion. This interaction is mediated by the basic domain of Tat (residues 48-57) and a conserved tryptophan (residue 11). After binding to PtdIns(4,5)P , Tat secretion diverges into multiple pathways, which we categorized as oligomerization-mediated pore formation, spontaneous translocation and incorporation into exosomes. Extracellular Tat has been shown to be neurotoxic and toxic to other cells of the central nervous system (CNS) and periphery, able to recruit immune cells to the CNS and cerebrospinal fluid, and alter the gene expression and morphology of uninfected cells. The effects of extracellular Tat have been examined in HIV-1-associated neurocognitive disorders (HAND); however, only a small number of studies have focused on the mechanisms underlying Tat secretion. In this review, the molecular mechanisms of Tat secretion will be examined in a variety of biologically relevant cell types.

helped create a map of the radiation oncology clinic. They received no compensation for their contribution. The Breast Cancer Research Foundation provided support staff.

Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/β-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit β-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to β-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of β-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of β-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect β-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.