title: Oocyte activation and latent HIV-1 reactivation: AMPK as a common mechanism of action linking the beginnings of life and the potential eradication of HIV-1.
abstract: In all mammalian species studied to date, the initiation of oocyte activation is orchestrated through alterations in intracellular calcium (Ca(2+)) signaling. Upon sperm binding to the oocyte plasma membrane, a sperm-associated phospholipase C (PLC) isoform, PLC zeta (PLCζ), is released into the oocyte cytoplasm. PLCζ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce diacylglycerol (DAG), which activates protein kinase C (PKC), and inositol 1,4,5-trisphosphate (IP3), which induces the release of Ca(2+) from endoplasmic reticulum (ER) Ca(2+) stores. Subsequent Ca(2+) oscillations are generated that drive oocyte activation to completion. Ca(2+) ionophores such as ionomycin have been successfully used to induce artificial human oocyte activation, facilitating fertilization during intra-cytoplasmic sperm injection (ICSI) procedures. Early studies have also demonstrated that the PKC activator phorbol 12-myristate 13-acetate (PMA) acts synergistically with Ca(2+) ionophores to induce parthenogenetic activation of mouse oocytes. Interestingly, the Ca(2+)-induced signaling cascade characterizing sperm or chemically-induced oocyte activation, i.e. the "shock and live" approach, bears a striking resemblance to the reactivation of latently infected HIV-1 viral reservoirs via the so called "shock and kill" approach, a method currently being pursued to eradicate HIV-1 from infected individuals. PMA and ionomycin combined, used as positive controls in HIV-1 latency reversal studies, have been shown to be extremely efficient in reactivating latent HIV-1 in CD4(+) memory T cells by inducing T cell activation. Similar to oocyte activation, T cell activation by PMA and ionomycin induces an increase in intracellular Ca(2+) concentrations and activation of DAG, PKC, and downstream Ca(2+)-dependent signaling pathways necessary for proviral transcription. Interestingly, AMPK, a master regulator of cell metabolism that is activated thorough the induction of cellular stress (e.g. increase in Ca(2+) concentration, reactive oxygen species generation, increase in AMP/ATP ratio) is essential for oocyte maturation, T cell activation, and mitochondrial function. In addition to the AMPK kinase LKB1, CaMKK2, a Ca(2+)/calmodulin-dependent kinase that also activates AMPK, is present in and activated on T cell activation and is also present in mouse oocytes and persists until the zygote and two-cell stages. It is our hypothesis that AMPK activation represents a central node linking T cell activation-induced latent HIV-1 reactivation and both physiological and artificial oocyte activation. We further propose the novel observation that various compounds that have been shown to reactivate latent HIV-1 (e.g. PMA, ionomycin, metformin, bryostatin, resveratrol, etc.) or activate oocytes (PMA, ionomycin, ethanol, puromycin, etc.) either alone or in combination likely do so via stress-induced activation of AMPK.
authors.affiliation: Finley BioSciences, Houston, TX 77042-4539, United States. Electronic address: jfinley4@alumni.jh.edu.
authors.forename: Jahahreeh
authors.initials: J
authors.lastname: Finley
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000628:therapy; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry; D015759:Ionomycin / Q000737:chemistry; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D009865:Oocytes / Q000166:cytology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013094:Spermatozoa / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D014775:Virus Activation
chemical_list: D004075:Diglycerides; D010716:Phosphatidylinositols; D015759:Ionomycin; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D010738:Type C Phospholipases; D002118:Calcium
keywords: AMP-activated protein kinase (AMPK); Bryostatin; CaMKK2; HIV-1 latency; Hutchinson–Gilford progeria syndrome (HGPS); LKB1; Metformin; Oocyte; Phospholipase C zeta (PLCζ); Phospholipase C-gamma 1 (PLCγ1); Resveratrol; Retinoic acid