title: Use of ATP analogs to inhibit HIV-1 transcription.
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.
authors: National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA 20110, USA.
authors: Aarthi
authors: A
authors: Narayanan
authors: Gavin
authors: G
authors: Sampey
authors: Rachel
authors: R
authors: Van Duyne
authors: Irene
authors: I
authors: Guendel
authors: Kylene
authors: K
authors: Kehn-Hall
authors: Jessica
authors: J
authors: Roman
authors: Robert
authors: R
authors: Currer
authors: Hervé
authors: H
authors: Galons
authors: Nassima
authors: N
authors: Oumata
authors: Benoît
authors: B
authors: Joseph
authors: Laurent
authors: L
authors: Meijer
authors: Massimo
authors: M
authors: Caputi
authors: Sergei
authors: S
authors: Nekhai
authors: Fatah
authors: F
authors: Kashanchi
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism*; D056906:Cyclin T / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D011687:Purines / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C503684:CCNT1 protein, human; C532131:CR8 compound; D056906:Cyclin T; D011687:Purines; D011725:Pyridines; D000255:Adenosine Triphosphate; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9