Facilitation of hippocampal long-term potentiation and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking learning, memory, and the potential eradication of HIV-1.

Learning and memory are generally considered the behavioral correlates of long-term potentiation (LTP), a form of synaptic plasticity associated with a persistent and long-lasting increase in synaptic strength. Repetitive stimulation of excitatory synapses in the hippocampal CA1 region leads to release and binding of glutamate to the glutamate receptors AMPAR and NMDAR located on pyramidal neurons. Activation of AMPARs facilitates Na+ influx, postsynaptic depolarization, NMDAR-mediated Ca2+ influx, and activation of several intracellular mechanisms that characterize LTP, including increased AMPAR synthesis, ROS production, and ER Ca2+ release. BDNF-TrkB receptor signaling, which increases intracellular Ca2+ levels via PLCγ1-mediated ER Ca2+ release, also plays an important role in facilitating hippocampal CA1 LTP. Interestingly, the cellular mechanisms that characterize LTP are strikingly similar to signaling pathways that underlie reactivation of latent HIV-1 reservoirs. Known as the "shock and kill" approach, reactivation of latent HIV-1, particularly in CD4+ memory T cells, is currently being pursued to potentially eradicate HIV-1. Indeed, AMPARs, NMDARs, and TrkB receptors have been found on and promote T cell activation and BDNF has been shown to reactivate latent HIV-1 in human macrophages. Additionally, latent HIV-1 reactivation via T cell receptor activation (a positive control in HIV-1 latency studies) involves PLCγ1-mediated increases in intracellular Ca2+, an increase in ROS levels, and activation of kinases and transcription factors that are also critical for LTP. Furthermore, PMA, also used as a positive control along with ionomycin in HIV-1 latency studies, has been shown to enhance hippocampal CA1 LTP. AMPK, an evolutionarily conserved kinase activated by increases in intracellular Ca2+, ROS, and/or AMP/ATP ratio increases improves lifespan and healthspan in several model organisms and is essential for T cell activation. Knockdown of AMPK also significantly inhibits HIV-1 replication. AMPK has been found localized in hippocampal CA1 dendrites and glutamate, NMDA, KCl, ionomycin, and BDNF have each been shown to induce AMPK activation in neurons. AMPK activation also increases synthesis and membrane insertion of AMPARs. Because both T cell activation and LTP are dependent on intracellular Ca2+ increases and because inhibition of ROS significantly inhibits hippocampal CA1 LTP and T cell activation, it is our hypothesis that AMPK links latent HIV-1 reactivation with hippocampal LTP, learning, and memory. We also propose that compounds that enhance or promote LTP and reactivate latent HIV-1 (e.g. PMA, ionomycin, resveratrol, metformin, etc.) either alone or in combination likely do so via AMPK activation.