title: The RIAD peptidomimetic inhibits HIV-1 replication in humanized NSG mice.
abstract: BACKGROUND
  Increased intracellular concentration of cyclic AMP (cAMP) in T cells is associated with various immunodeficiency conditions including human immunodeficiency virus (HIV) infection. Several reports indicate a critical role of activated protein kinase A (PKA) in the susceptibility of cells to HIV infection. We have used a cell permeable, stable peptidomimetic version (P3) of the RI-anchoring disruptor (RIAD), which prevents PKA interaction with A-kinase-anchoring proteins (AKAPs). It is known that RIAD peptide abrogates effects of localized cAMP signalling through anchored type I PKA in lymphocytes and prevents murine AIDS (MAIDS) infection when expressed as a transgene in mice.
  
  
  RESULTS
  In vitro HIV-infected human peripheral blood mononuclear cells (PBMCs) show reduced levels of p24 and intracellular cAMP in T cells when treated with RIAD peptidomimetic (RIAD-P3). Humanized NOD/SCID/IL2γnull (NSG) mice infected with HIV-1 JRCSF and treated with RIAD-P3 (3·5 mg) once every 2 weeks showed significantly reduced levels of viral load at +28, +42 and +56 days and increased CD4 numbers at +56 days after the start of treatment. RIAD-P3-treated humanized mice had lower levels of intracellular cAMP in T cells sorted from splenocytes.
  
  
  CONCLUSIONS
  Treatment with RIAD-P3 limits HIV-1 viral replication and stabilizes CD4 levels by mechanisms involving cAMP/PKA-I pathway in human PBMCs and humanized NSG mice.
authors.affiliation: Immunology & Infectious Diseases, CHU de Liège, Université de Liège, Liège, Belgium.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Singh
authors.forename: Pratibha
authors.initials: P
authors.lastname: Singh
authors.forename: Dolores
authors.initials: D
authors.lastname: Vaira
authors.forename: Eirik A
authors.initials: EA
authors.lastname: Torheim
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000821:virology; D016513:Mice, SCID; D008822:Mice, Transgenic; D057786:Peptidomimetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D054758:A Kinase Anchor Proteins; D016655:HIV Core Protein p24; D047908:Intracellular Signaling Peptides and Proteins; D057786:Peptidomimetics; C015482:protein kinase modulator; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: HIV; NOD/LtsZ-scidIL-2Rγnull mice; RIAD peptidomimetic; cAMP