Regulation of HIV-1 transcription at 3% versus 21% oxygen concentration.
HIV transcription is induced by the HIV-1 Tat protein, in concert with cellular co-factors including CDK9, CDK2, NF-kappaB, and others. The cells of most of the body's organs are exposed to approximately 3-6% oxygen, but most in vitro studies of HIV replication are conducted at 21% oxygen. We hypothesized that activities of host cell factors involved in HIV-1 replication may differ at 3% versus 21% O(2), and that such differences may affect HIV-1 replication. Here we show that Tat-induced HIV-1 transcription was reduced at 3% O(2) compared to 21% O(2). HIV-1 replication was also reduced in acutely or chronically infected cells cultured at 3% O(2) compared to 21% O(2). This reduction was not due the decreased cell growth or increased cellular toxicity and also not due to the induction of hypoxic response. At 3% O(2), the activity of CDK9/cyclin T1 was inhibited and Sp1 activity was reduced, whereas the activity of other host cell factors such as CDK2 or NF-kappaB was not affected. CDK9-specific inhibitor ARC was much less efficient at 3% compared to 21% O(2) and also expression of CDK9/cyclin T1-dependent IkappaB inhibitor alpha was repressed. Our results suggest that lower HIV-1 transcription at 3% O(2) compared to 21% O(2) may be mediated by lower activity of CDK9/cyclin T1 and Sp1 at 3% O(2) and that additional host cell factors such as CDK2 and NF-kappaB might be major regulators of HIV-1 transcription at low O(2) concentrations.
Charles
Sharroya
S
Center for Sickle Cell Disease, Howard University, Washington, DC 20001, USA.
Ammosova
Tatyana
T
Cardenas
Jessica
J
Foster
Altreisha
A
Rotimi
Jamie
J
Jerebtsova
Marina
M
Ayodeji
Abisola A
AA
Niu
Xiaomei
X
Ray
Patricio E
PE
Gordeuk
Victor R
VR
Kashanchi
Fatah
F
Nekhai
Sergei
S
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056906:Cyclin T; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D010100:Oxygen