Iκκ mediates NF-κB activation in human immunodeficiency virus- infected cells

Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Journal of Virology (Impact Factor: 4.44). 06/1999; 73(5):3893-903.
Source: PubMed


Human monocytes and macrophages are persistent reservoirs of human immunodeficiency virus (HIV) type-1. Persistent HIV infection of these cells results in increased levels of NF-kappaB in the nucleus secondary to increased IkappaBalpha, IkappaBbeta, and IkappaBepsilon degradation, a mechanism postulated to regulate viral persistence. To characterize the molecular mechanisms regulating HIV-mediated degradation of IkappaB, we have sought to identify the regulatory domains of IkappaBalpha targeted by HIV infection. Using monocytic cells stably expressing different transdominant molecules of IkappaBalpha, we determined that persistent HIV infection of these cells targets the NH2 but not the COOH terminus of IkappaBalpha. Further analysis demonstrated that phosphorylation at S32 and S36 is necessary for HIV-dependent IkappaBalpha degradation and NF-kappaB activation. Of the putative N-terminal IkappaBalpha kinases, we demonstrated that the Ikappakappa complex, but not p90(rsk), is activated by HIV infection and mediates HIV-dependent NF-kappaB activation. Analysis of viral replication in cells that constitutively express IkappaBalpha negative transdominant molecules demonstrated a lack of correlation between virus-induced NF-kappaB (p65/p50) nuclear translocation and degree of viral persistence in human monocytes.

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    • "Another strategy that allows the virus to infect and persist in macrophages is the resistance to apoptosis. The NF-κB pathway is activated upon HIV-1 infection in primary monocytes and macrophages [127, 128]. It has been proposed that TNF-α-induced NF-κB activity might be involved in the inhibition of apoptosis and the survival of monocytes and macrophages. "
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    Advances in Virology 04/2012; 2012(74):574967. DOI:10.1155/2012/574967
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    • "It has been proposed that TNFα-induced NF-kB activity might be involved in the inhibition of apoptosis and the survival of monocytes and macrophages even if Tumour Necrosis Factor alpha (TNFα) is best known as a pro-inflammatory mediator capable to induce apoptosis. Persistent HIV-1 infection of macrophages results in increased levels of the transcription factor nuclear factor kappa B (NF-κB) in the nucleus secondary to increased IκBα, IκBβ, and IκBε degradation, a mechanism postulated to regulate viral persistence [135,136]. NF-κB is involved in the resistance to TNF-induced apoptosis that might result in a decreased susceptibility to apoptosis of macrophage versus T cells in the context of chronic immune activation like in HIV-1 infection. This indicates clearly that HIV-1 can manipulate the apoptotic machinery to its advantage. "
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    • "Multiple stimuli are capable of activating NF-κB including, but not limited to, proinflammatory cytokines (e.g., TNF-α), activating cellular receptors (e.g., TCR), viral proteins (e.g., EBV-LMP-1), DNA cleavage, chemotherapeutics (doxorubicin), and oxidative stress. We have previously assessed the involvement of NF-κB family members in HIV replication that occurs during the peak of virus-induced death by demonstrating that a super repressor form of IKBα blocks HIV replication, thereby implicating NF-κB family members as the dominant transcriptional mechanism that drives such HIV replication [20]. We next asked whether gp120-induced HIV replication is mediated by transcriptional upregulation. "
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