Kaposi's sarcoma associated herpes virus-encoded viral FLICE inhibitory protein activates transcription from HIV-1 Long Terminal Repeat via the classical NF-κB pathway and functionally cooperates with Tat

Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Retrovirology (Impact Factor: 4.19). 02/2005; 2(1):9. DOI: 10.1186/1742-4690-2-9
Source: PubMed


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.
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.
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.

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    ABSTRACT: Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is discovered in 1994 from Kaposi’s sarcoma (KS) lesion of an acquired immunodeficiency syndrome (AIDS) patient. In addition to its association with KS, KSHV has also been implicated as the causative agent of two other AIDS-associated malignancies: primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). KSHV is a complex DNA virus that not only has the ability to promote cellular growth and survival for tumor development, but also can provoke deregulated angiogenesis, inflammation, and modulate the patient’s immune system in favor of tumor growth. As KSHV is a necessary but not sufficient etiological factor for KS, human immunodeficiency virus (HIV) is a very important cofactor. Here we review the basic information about the biology of KSHV, development of pathogenesis and interaction between KSHV and HIV.
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    ABSTRACT: Human herpesvirus 8 (HHV-8) encodes a viral FLICE inhibitory protein (vFLIP), called K13, with homology to the prodomain of caspase 8. K13 has been postulated to protect virally infected cells against death receptor-induced apoptosis. We report that K13 leads to constitutive upregulation of IL-8 secretion by transcriptional upregulation of its promoter. K13-induced IL-8 promoter activation is dependent on an intact NF-kappaB-binding site and is associated with increased binding of classical NF-kappaB pathway subunits p65, c-Rel and p50, respectively. IL-8 production is defective in K13 mutants defective in classical NF-kappaB activation and is blocked by genetic and pharmacological inhibitors of this pathway. In contrast, K13 failed to activate the JNK/AP-1 pathway and deletion of AP-1-binding site in the IL-8 promoter or use of a specific JNK inhibitor had only a partial effect on K13-induced IL-8 promoter activation. Collectively, above results demonstrate that K13 is a major mediator of IL-8 production and therapeutic agents targeting K13-induced NF-kappaB pathway may have a role in the treatment of conditions in which HHV-8-induced IL-8 production plays a pathogenic role.
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