title: Inhibition of HIV Expression and Integration in Macrophages by Methylglyoxal-Bis-Guanylhydrazone.
abstract: Macrophages are a target for infection with HIV and represent one of the viral reservoirs that are relatively resistant to current antiretroviral drugs. Here we demonstrate that methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine analog and potent S-adenosylmethionine decarboxylase inhibitor, decreases HIV expression in monocytes and macrophages. MGBG is selectively concentrated by these cells through a mechanism consistent with active transport by the polyamine transporter. Using a macrophage-tropic reporter virus tagged with the enhanced green fluorescent protein, we demonstrate that MGBG decreases the frequency of HIV-infected cells. The effect is dose dependent and correlates with the production of HIV p24 in culture supernatants. This anti-HIV effect was further confirmed using three macrophage-tropic primary HIV isolates. Viral life cycle mapping studies show that MGBG inhibits HIV DNA integration into the cellular DNA in both monocytes and macrophages.
  
  
  OBJECTIVE
  Our work demonstrates for the first time the selective concentration of MGBG by monocytes/macrophages, leading to the inhibition of HIV-1 expression and a reduction in proviral load within macrophage cultures. These results suggest that MGBG may be useful in adjunctive macrophage-targeted therapy for HIV infection.
authors.affiliation: Pathologica LLC, Burlingame, California, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Jin
authors.affiliation: UCSF Department of Laboratory Medicine, Medicine, and Pathology; AIDS & Cancer Specimen Resource, San Francisco General Hospital, San Francisco, California, USA mmcgrath@hemeonc.ucsf.edu hua@synergenics.net.
authors.forename: Michael S
authors.initials: MS
authors.lastname: McGrath
authors.affiliation: Pathologica LLC, Burlingame, California, USA mmcgrath@hemeonc.ucsf.edu hua@synergenics.net.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D001693:Biological Transport, Active; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000821:virology*; D008935:Mitoguazone / Q000494:pharmacology*; D009000:Monocytes / Q000821:virology*; D019713:Receptors, CCR5 / Q000096:biosynthesis; D016662:Virus Integration / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D044966:Anti-Retroviral Agents; C584933:CCR5 protein, human; D015704:CD4 Antigens; D016655:HIV Core Protein p24; D018950:Lipopolysaccharide Receptors; D019713:Receptors, CCR5; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012437:Adenosylmethionine Decarboxylase; D008935:Mitoguazone