HIV gp120 induces, NF-κB 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


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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    • "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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    • "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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