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

• Published in: AIDS research and human retroviruses Vol. 28; no. 2; p. 182
• Main Authors: Toossi, Zahra, Wu, Mianda, Hirsch, Christina S, Mayanja-Kizza, Harriet, Baseke, Joy, Aung, Htin, Canaday, David H, Fujinaga, Koh
• Format: Journal Article
• Language: English
• Published: United States 01.02.2012
• Subjects: Adult; Blotting, Western; Coinfection; Cyclin T - drug effects; Female; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - metabolism; HIV-1 - drug effects; HIV-1 - physiology; Humans; Indoles - pharmacokinetics; Male; Middle Aged; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Oximes - pharmacokinetics; Positive Transcriptional Elongation Factor B - drug effects; Positive Transcriptional Elongation Factor B - genetics; Positive Transcriptional Elongation Factor B - metabolism; Transcriptional Activation - drug effects; Tuberculosis - drug therapy; Tuberculosis - genetics; Tuberculosis - metabolism; Uganda - epidemiology; Virus Replication - drug effects; Uganda
• ISSN: 1931-8405
• DOI: 10.1089/AID.2010.0211

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.