title: Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcriptional activation by the inhibitor of CDK9, Indirubin-3'-monoxime.
abstract: At sites of Mycobacterium tuberculosis (MTB) infection, HIV-1 replication is increased during tuberculosis (TB). Here we investigated the role of positive transcription elongation factor (P-TEFb), comprised of CycT1 and CDK9, as the cellular cofactor of HIV-1 Tat protein in transcriptional activation of HIV-1 in mononuclear cells from HIV-1-infected patients with pleural TB. Expression of CycT1 in response to MTB was assessed in mononuclear cells from pleural fluid (PFMC) and blood (PBMC) from HIV/TB patients with pleural TB, and in blood monocytes (MN) from singly infected HIV-1-seropositive subjects. We then examined whether the CDK9 inhibitor, Indirubin 3'-monoxime (IM), was effective in inhibition of MTB-induced HIV-1 mRNA expression. We found higher expression of CycT1 mRNA in PFMCs as compared to PBMCs from HIV/TB-coinfected subjects. MTB induced the expression of CycT1 and HIV-1 gag/pol mRNA in both PFMCs from HIV/TB subjects and MN from HIV-1-infected subjects. CycT1 protein was also induced by MTB stimulation in PFMCs from HIV/TB patients, and both MN and in vitro-derived macrophages. Inhibition of CDK9 by IM in both PFMCs from HIV/TB and MN from HIV-1-infected subjects in response to MTB led to inhibition of HIV-1 mRNA expression. These data imply that IM may be useful as an adjunctive therapy in control of HIV-1 replication in HIV/TB dually infected subjects.
authors: Case Western Reserve University, Cleveland, Ohio 44106-4984, USA. zahra.toossi@case.edu
authors: Zahra
authors: Z
authors: Toossi
authors: Mianda
authors: M
authors: Wu
authors: Christina S
authors: CS
authors: Hirsch
authors: Harriet
authors: H
authors: Mayanja-Kizza
authors: Joy
authors: J
authors: Baseke
authors: Htin
authors: H
authors: Aung
authors: David H
authors: DH
authors: Canaday
authors: Koh
authors: K
authors: Fujinaga
mesh_terms: D000328:Adult; D015153:Blotting, Western; D060085:Coinfection; D056906:Cyclin T / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010091:Oximes / Q000493:pharmacokinetics*; D042925:Positive Transcriptional Elongation Factor B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014454:Uganda / Q000453:epidemiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D056906:Cyclin T; D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; D042925:Positive Transcriptional Elongation Factor B