Kaposi's sarcoma associated herpes virus-encoded viral FLICE inhibitory protein activates transcription from HIV-1 Long Terminal Repeat via the classical NF-kappaB pathway and functionally cooperates with Tat.
BACKGROUND
The nuclear transcription factor NF-kappaB binds to the HIV-1 long terminal repeat (LTR) and is a key regulator of HIV-1 gene expression in cells latently infected with this virus. In this report, we have analyzed the ability of Kaposi's sarcoma associate herpes virus (KSHV, also known as Human Herpes virus 8)-encoded viral FLIP (Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein) K13 to activate the HIV-1 LTR.


RESULTS
We present evidence that vFLIP K13 activates HIV-1 LTR via the activation of the classical NF-kappaB pathway involving c-Rel, p65 and p50 subunits. K13-induced HIV-1 LTR transcriptional activation requires the cooperative interaction of all three components of the IKK complex and can be effectively blocked by inhibitors of the classical NF-kappaB pathway. K13 mutants that lacked the ability to activate the NF-kappaB pathway also failed to activate the HIV-1 LTR. K13 could effectively activate a HIV-1 LTR reporter construct lacking the Tat binding site but failed to activate a construct lacking the NF-kappaB binding sites. However, coexpression of HIV-1 Tat with K13 led to synergistic activation of HIV-1 LTR. Finally, K13 differentially activated HIV-1 LTRs derived from different strains of HIV-1, which correlated with their responsiveness to NF-kappaB pathway.


CONCLUSIONS
Our results suggest that concomitant infection with KSHV/HHV8 may stimulate HIV-1 LTR via vFLIP K13-induced classical NF-kappaB pathway which cooperates with HIV-1 Tat protein.
Sun
Qinmiao
Q
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390-8593, USA. qinmiao.sun@utsouthwestern.edu
Matta
Hittu
H
Chaudhary
Preet M
PM
D000818:Animals; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000378:metabolism*; D016325:HIV Long Terminal Repeat / Q000235:genetics / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D015696:Gene Products, tat; D016328:NF-kappa B; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8