Role of p38 mitogen-activated protein kinase in HIV type 1 production
            <i>in vitro</i>

Shapiro, Leland; Heidenreich, Kim A.; Meintzer, Mary Kay; Dinarello, Charles A.

doi:10.1073/pnas.95.13.7422

Cited by 91 publications

(78 citation statements)

References 28 publications

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“…An increasing amount of information has demonstrated that many viruses activate the p38 MAPK pathway to augment their efficient replication (51)(52)(53)(54)(55). To this end, although in our earlier study we have demonstrated that p38 MAPK activation is beneficial for ARV replication (31), its precise role in regulating ARV entry and replication remains elusive so far.…”

Section: Discussionmentioning

confidence: 91%

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Huang

Wang

et al. 2011

Journal of Biological Chemistry

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Very little is known about the mechanism of cell entry of avian reovirus (ARV). The aim of this study was to explore the mechanism of ARV entry and subsequent infection. Cholesterol mainly affected the early steps of the ARV life cycle, because the presence of cholesterol before and during viral adsorption greatly blocked ARV infectivity. Although we have demonstrated that ARV facilitating p38 MAPK is beneficial for virus replication, its mechanism remains unknown. Here, we show that ARV-induced phosphorylation of caveolin-1 (Tyr 14 ), dynamin-2 expression, and Rac1 activation through activation of p38 MAPK and Src in the early stage of the virus life cycle is beneficial for virus entry and productive infection. The strong inhibition by dynasore, a specific inhibitor of dynamin-2, and depletion of endogenous caveolin-1 or dynamin-2 by siRNAs as well as the caveolin-1 colocalization study implicate caveolin-1-mediated and dynamin-2-dependent endocytosis as a significant avenue of ARV entry. By means of pharmacological inhibitors, dominant negative mutants, and siRNA of various cellular proteins and signaling molecules, phosphorylation of caveolin-1, dynamin-2 expression, and Rac1 activation were suppressed, suggesting that by orchestrating p38 MAPK, Src, and Rac1 signaling cascade in the target cells, ARV creates an appropriate intracellular environment facilitating virus entry and productive infection. Furthermore, disruption of microtubules, Rab5, or endosome acidification all inhibited ARV infection, suggesting that microtubules and small GTPase Rab5, which regulate transport to early endosome, are crucial for survival of ARV and that exposure of the virus to acidic pH is required for productive infection.

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Section: Discussionmentioning

confidence: 91%

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Huang

Wang

et al. 2011

Journal of Biological Chemistry

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“…However, R5 envelopes were more pronounced in their capacity to modulate the p38 MAPK cascade. The expression of p38 MAPK has been shown to positively correlate with HIV replication (37) and inhibitors of p38 kinase inhibit viral replication (37,38). Thus, the more pronounced activation of genes included in the p38 signaling cascade identifies one potential mechanism that favors R5 viral replication.…”

Section: Discussionmentioning

confidence: 99%

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

Cicala

Arthos²,

Martinelli³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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HIV envelope binds to and signals through its primary cellular receptor, CD4, and through a coreceptor, either CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4). Here, we evaluate the response of peripheral blood mononuclear cells to a panel of genetically diverse R5 and X4 envelope proteins. Modulation of gene expression was evaluated by using oligonucleotide microarrays. Activation of transcription factors was evaluated by using an array of oligonucleotides encoding transcription factor binding sites. Responses were strongly influenced by coreceptor specificity. Treatment of cells from CCR5⌬32 homozygous donors with glycoprotein (gp)120 derived from an R5 virus demonstrated that the majority of responses elicited by R5 envelopes required engagement of CCR5. R5 envelopes, to a greater extent than X4 envelopes, induced the expression of genes belonging to mitogenactivated protein kinase signal transduction pathways and genes regulating the cell cycle. A number of genes induced by R5, but not X4, envelopes were also up-regulated in the resting CD4 ؉ T cell population of HIV-infected individuals. These results suggest that R5 envelope facilitates replication of HIV in the pool of resting CD4 ؉ T cells. Additionally, signaling by R5 gp120 may facilitate the transmission of R5 viruses by inducing a permissive environment for HIV replication.ϩ T cells begins with the fusion of the viral envelope with the outer membrane of a target cell. Fusion is initiated when the viral envelope glycoprotein (gp)120 binds first to CD4 and then to a coreceptor, primarily CC chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4) (1-4). These interactions between gp120 and cell-surface receptors transduce signals in the target cell. Ligation of CD4 by gp120 increases the tyrosine kinase activity of p56lck, a src-related protein kinase associated with the cytoplasmic domain of CD4 on CD4 ϩ T cell membranes (5). Engagement of CCR5 and CXCR4 by gp120 also mediates signaling events (6-9), as evidenced by the rapid mobilization of Ca ϩϩ , and the phosphorylation of intracellular substrates including PYK2 and FAK (10,11). In this respect, the HIV envelope protein delivers a unique near simultaneous dual signal to CD4 ϩ T cells. No protein in the human proteome has been shown to deliver an analogous signal. The response to this stimulus depends on the state of differentiation and activation of the targeted cell. A number of reports demonstrate that envelope induces activated CD4 ϩ T cells to apoptose in vitro (12-15). Envelope proteins have also been shown to disrupt antigen-specific CD4 ϩ T cell responses (16). We have focused on the impact of envelope-mediated signaling on resting CD4 ϩ T cells. These cells constitute one of the latent reservoirs of HIV that prevents eradication of virus from infected individuals, even after prolonged treatment with potent antiretroviral drugs (17,18). In vitro exposure of resting CD4 ϩ T cells derived from HIV-infected individuals to envelope results in a burst of viral replicatio...

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“…IL-32 affects NF-B and p38MAPK in macrophages and T cells, the target cells of HIV-1. In addition, IL-32-induced IL-1␤, TNF-␣, IL-6, and chemokines (IL-8 and MIP-2) (2) are each relevant to the pathoimmunology of HIV-1 (14,15). We therefore investigated the role of this new cytokine in infection with HIV-1.…”

mentioning

confidence: 99%

Endogenous IL-32 Controls Cytokine and HIV-1 Production

Nold

Nold-Petry

Pott

et al. 2008

The Journal of Immunology

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114

148

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IL-32, a proinflammatory cytokine that activates the p38MAPK and NF-κB pathways, induces other cytokines, for example, IL-1β, IL-6, and TNF-α. This study investigated the role of endogenous IL-32 in HIV-1 infection by reducing IL-32 with small interfering (si)RNA in freshly infected PBMC and in the latently infected U1 macrophage cell line. When PBMC were pretreated with siRNA to IL-32 (siIL-32), IL-6, IFN-γ, and TNF-α were reduced by 57, 51, and 36%, respectively, compared with scrambled siRNA. Cotransfection of NF-κB and AP-1 reporter constructs with siIL-32 decreased DNA binding of these transcription factors by 42 and 46%, respectively. Cytokine protein array analysis revealed that the inhibitory activity of siIL-32 primarily targeted Th1 and proinflammatory cytokines and chemokines, e.g., MIP-1α/β. Unexpectedly, HIV-1 production (as measured by p24) increased 4-fold in these same PBMC when endogenous IL-32 was reduced. Because IFN-γ was lower in siIL-32-treated PBMC, we blocked IFN-γ bioactivity, which enhanced the augmentation of p24 by siIL-32. Furthermore, siIL-32 reduced the natural ligands of the HIV-1 coreceptors CCR5 (MIP-1α/β and RANTES) and CXCR4 (SDF-1). Inhibition of endogenous IL-32 in U1 macrophages also increased HIV-1. When rhIL-32γ was added to these cells, p24 levels fell by 72%; however, in the same cultures IFN-α increased 4-fold. Blockade of IFN-α/β bioactivity in IL-32γ-stimulated U1 cells revealed that IFN-α conveys the anti-HIV-1 effect of rhIL-32γ. In summary, depletion of endogenous IL-32 reduced the levels of Th1 and proinflammatory cytokines but paradoxically increased p24, proposing IL-32 as a natural inhibitor of HIV-1.

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Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro

Cited by 91 publications

References 28 publications

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells

Endogenous IL-32 Controls Cytokine and HIV-1 Production

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