Use of ATP analogs to inhibit HIV-1 transcription

• Published in: Virology (New York, N.Y.) Vol. 432; no. 1; pp. 219 - 231
• Main Authors: Narayanan, Aarthi, Sampey, Gavin, Van Duyne, Rachel, Guendel, Irene, Kehn-Hall, Kylene, Roman, Jessica, Currer, Robert, Galons, Hervé, Oumata, Nassima, Joseph, Benoît, Meijer, Laurent, Caputi, Massimo, Nekhai, Sergei, Kashanchi, Fatah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2012
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Antiviral Agents - metabolism; ATP analog; cdk9; Cyclin T - metabolism; Cyclin T1; Cyclin-Dependent Kinase 9 - metabolism; HIV-1; HIV-1 - drug effects; HIV-1 - physiology; Humans; Infectious Disease; Purines - metabolism; Pyridines - metabolism; Tat; Transcription; Transcription, Genetic - drug effects; HIV-1; cdk9; ATP analog; Transcription; Cyclin T1; Tat
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2012.06.007

Abstract Human immunodeficiency virus type 1 (HIV-1) is the etiological agent of AIDS. Chronic persistent infection is an important reason for the presence of “latent cell populations” even after Anti-Retroviral Therapy (ART). We have analyzed the effect of ATP analogs in inhibiting cdk9/T1 complex in infected cells. A third generation drug named CR8#13 is an effective inhibitor of Tat activated transcription. Following drug treatment, we observed a decreased loading of cdk9 onto the HIV-1 DNA. We found multiple novel cdk9/T1 complexes present in infected and uninfected cells with one complex being unique to infected cells. This complex is sensitive to CR8#13 in kinase assays. Treatment of PBMC with CR8#13 does not kill infected cells as compared to Flavopiridol. Interestingly, there is a difference in sensitivity of various clades to these analogs. Collectively, these results point to targeting novel complexes for inhibition of cellular proteins that are unique to infected cells.