HIV gp120 induces, NF-kappaB dependent, HIV replication that requires procaspase 8.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(3):e4875. DOI: 10.1371/journal.pone.0004875
Source: PubMed

ABSTRACT HIV envelope glycoprotein gp120 causes cellular activation resulting in anergy, apoptosis, proinflammatory cytokine production, and through an unknown mechanism, enhanced HIV replication.
We describe that the signals which promote apoptosis are also responsible for the enhanced HIV replication. Specifically, we demonstrate that the caspase 8 cleavage fragment Caspase8p43, activates p50/p65 Nuclear Factor kappaB (NF-kappaB), in a manner which is inhibited by dominant negative IkappaBalpha. This caspase 8 dependent NF-kappaB activation occurs following stimulation with gp120, TNF, or CD3/CD28 crosslinking, but these treatments do not activate NF-kappaB in cells deficient in caspase 8. The Casp8p43 cleavage fragment also transactivates the HIV LTR through NF-kappaB, and the absence of caspase 8 following HIV infection greatly inhibits HIV replication.
Gp120 induced caspase 8 dependent NF-kappaB activation is a novel pathway of HIV replication which increases understanding of the biology of T-cell death, as well as having implications for understanding treatment and prevention of HIV infection.

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    • "In the case of HIV-1, several viral components have been shown to stimulate the NF-kB pathway (Santoro et al., 2003). These include HIV-1 RNA, viral gp120, gp41, Tat and Nef (Bren et al., 2009; Demarchi et al., 1999; Fortin et al., 2004; Ishii et al., 2001; Mingyan et al., 2009; Postler and Desrosiers, 2012). The outcome of activating the NF-kB pathway is the transactivation of the HIV-1 LTR and increase in viral gene expression. "
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    ABSTRACT: The human immunodeficiency virus type I (HIV-1) Vpr plays an essential role in viral replication. A number of studies have reported that Vpr modulates the nuclear factor-κB (NF-κB) pathway. Yet, the reported effects of Vpr on NF-κB signaling are controversial. In this study, we investigate the interplay between Vpr and NF-κB pathway. We discover that HIV-1 infection elevates the phosphorylation of IκBα and p100, and that this increase is greatly reduced when a Vpr-negative HIV-1 is used for infection. Our data further show that Vpr regulates the activity of IKKα/β through interactions. In addition, Vpr modulates the phosphorylation of p65 and p100, suggesting that Vpr activates both canonical and noncanonical NF-κB pathway. Knock down of endogenous IKKα/β result in a decrease in Vpr-mediated NF-κB and HIV-1 LTR activation. Given that Vpr is present in HIV-1 particles, our data suggest that Vpr activates the NF-κB pathway immediately after HIV-1 entry.
    Virology 02/2013; 439(1). DOI:10.1016/j.virol.2013.01.020 · 3.32 Impact Factor
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    • "In fact, HIV replication is (1) increased in immortalized T cell lines induced to express pro-apoptotic proteins (FasL, FADD [Fas-associated death domain protein], and p53); (2) decreased in cells overexpressing anti-apoptotic proteins (Bcl-2, FLIP [FLICE-inhibitory protein], Bcl-XL, and XIAP [X-linked inhibitor of apoptosis protein]); (3) decreased in cells with knockdown of pro-apoptotic proteins (Bax and FADD); and (4) decreased in the setting of inhibition of caspase 3 activity [4–6]. Importantly, treatment with the HIV envelope protein Gp120 or expression of Casp8p41 (a unique cleavage fragment of procaspase 8 generated by HIV protease), both of which are associated with HIV-induced apoptosis, increases NF-κB-dependent HIV-LTR (long terminal repeat) transcription compared to untreated cells or cells treated with control proteins [7, 8]. This suggests that the critical link between HIV-induced apoptosis and replication is in activation of NF-κB, through a caspase 8-dependent mechanism, a survival mechanism that has been co-opted by a number of other viruses [9]. "
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    ABSTRACT: Past efforts at curing infection with the human immunodeficiency virus (HIV) have been blocked by the resistance of some infected cells to viral cytopathic effects and the associated development of a latent viral reservoir. Furthermore, current efforts to clear the viral reservoir by means of reactivating latent virus are hampered by the lack of cell death in the newly productively infected cells. The purpose of this review is to describe the many anti-apoptotic mechanisms of HIV, as well as the current limitations in the field. Only by understanding how infected cells avoid HIV-induced cell death can an effective strategy to kill infected cells be developed.
    Cellular and Molecular Life Sciences CMLS 12/2012; 70(18). DOI:10.1007/s00018-012-1239-3 · 5.81 Impact Factor
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    • "In HIV-1 entry, the binding of the gp120 viral envelope to CD4 induces the NF-κB activity by activation of IKK (30) and procaspase 8 (31). Following viral integration, the early encoded HIV-1 Tat protein interacts with the HIV-1 RNA and host cell factors to sustain the viral replication. "
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    ABSTRACT: Nuclear factor (NF)-κB is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-κB deregulation by HIV-1 are relevant for immune dysfunction in AIDS. We report that in single round HIV-1 infection, or single-pulse PMA stimulation, the HIV-1 Tat transactivator activated NF-κB by hijacking the inhibitor IκB-α and by preventing the repressor binding to the NF-κB complex. Moreover, Tat associated with the p65 subunit of NF-κB and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for IκB-α and p65 association, respectively, and for sustaining the NF-κB activity. Among an array of NF-κB-responsive genes, Tat mostly activated the MIP-1α expression in a p65-dependent manner, and bound to the MIP-1α NF-κB enhancer thus promoting the recruitment of p65 with displacement of IκB-α; similar findings were obtained for the NF-κB-responsive genes CSF3, LTA, NFKBIA and TLR2. Our results support a novel mechanism of NF-κB activation via physical interaction of Tat with IκB-α and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1.
    Nucleic Acids Research 12/2011; 40(8):3548-62. DOI:10.1093/nar/gkr1224 · 9.11 Impact Factor
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