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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating protein-1 (AP-1) binding phorbol ester responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind cFos and junD and transmit protein kinase C (PKC) activation signals to the LTR. Further studies suggested the DSE might also bind AP-1-related proteins of the CREB/ATF family. Since enhanced HIV-1 expression is associated with activation of the cAMP-dependent protein kinase A (PKA) signaling pathway, we determined whether binding of CREB/ATF proteins to the DSE mediate cAMP/PKA activation of the HIV-1 LTR. In the present study. DSE binding complexes in nuclear protein extracta from colonic epithelial cells are shown to contain ATF-1, ATF-2, and CREB and transfection of either an ATF-2 or PKA expressing plasmid transactivated the DSE. Cholera toxin (Ctx), a potent activator of the cAMP/PKA pathway. Increased HIV-1 virus production from a latently infected promonocytic cell line, U1. Ctx increased LTR promoter activity and increased the CREB content of DSE binding complexes. Transfection of U1 cells with a series of mutant LTR reporter constructs demonstrated that the Ctx response was in large part mediated by the DSE. The Ctx response was also mediated by a heterologous promoter containing multiple TRE sites. Nuclear protein extracts from a T-cell line infected by HIV-1 contained higher levels of CREB/ATF proteins and manifested increased CREB/ATF binding activity. Collectively, these results indicate the DSE are TRE-like cAMP responsive elements that bind both AP-1 and CREB/ATF permitting induction of the HIV-1 LTR by both PKC and PKA activation signals.
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PMID:U5 region of the human immunodeficiency virus type 1 long terminal repeat contains TRE-like cAMP-responsive elements that bind both AP-1 and CREB/ATF proteins. 920 Dec 33

NF-kappa B/Rel transcription factors participate in the activation of numerous genes involved in immune regulation/inflammation including cytokines, cell surface receptors, adhesion molecules, and acute phase proteins. NF-kappa B activity is controlled by inhibitory proteins, I kappa Bs, that maintain the DNA-binding forms of NF-kappa B in an inactive state in the cytoplasm. Many viruses, including the human retroviruses HIV-1 and HTLV-1, also utilize the NF-kappa B/I kappa B pathway to their transcriptional advantage during viral infection. Our recent studies have focused on the I kappa B alpha inhibitor and have characterized several protein interactions that modulate the functional activity of I kappa B alpha during human retrovirus infection. In this article, we summarise recent studies demonstrating that (1) chronic HIV-1 infection of human myelomonoblastic PLB-985 cells leads to constitutive NF-kappa B activity, activated in part due to enhanced I kappa B alpha turnover and increased NF-kappa B/Rel production; (2) HTLV-1 Tax protein physically associates with the I kappa B alpha protein in vivo and in vitro and also mediates a 20- to 40-fold stimulation of NF-kappa B DNA binding activity mediated via an enhancement of NF-kappa B dimer formation; (3) casein kinase II phosphorylates I kappa B alpha at multiple sites in the C-terminal PEST domains and regulates I kappa B alpha function; (4) transdominant forms of I kappa B alpha, mutated in critical Ser or Thr residues required for inducer-mediated (S32A,S36A) and/or constitutive phosphorylation block HIV LTR trans-activation and also effectively inhibit HIV-1 multiplication in a single cycle infection model; and (5) the amino-terminal 55aa of I kappa B alpha (NIK) interacts with the human homologue of dynein light chain 1, a small 9-kDa human homologue of the dynein light chain protein involved in microtubule and cytoskeletal dynamics. Together, our results highlight a number of intriguing molecular interactions between I kappa B alpha and cellular or viral proteins that modulate transcription factor activity and nuclear-cytoplasmic flow of host proteins.
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PMID:Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection. 922 98

P-TEFb is a key regulator of the process controlling the processivity of RNA polymerase II and possesses a kinase activity that can phosphorylate the carboxy-terminal domain of the largest subunit of RNA polymerase II. Here we report the cloning of the small subunit of Drosophila P-TEFb and the finding that it encodes a Cdc2-related protein kinase. Sequence comparison suggests that a protein with 72% identity, PITALRE, could be the human homolog of the Drosophila protein. Functional homology was suggested by transcriptional analysis of an RNA polymerase II promoter with HeLa nuclear extract depleted of PITALRE. Because the depleted extract lost the ability to produce long DRB-sensitive transcripts and this loss was reversed by the addition of purified Drosophila P-TEFb, we propose that PITALRE is a component of human P-TEFb. In addition, we found that PITALRE associated with the activation domain of HIV-1 Tat, indicating that P-TEFb is a Tat-associated kinase (TAK). An in vitro transcription assay demonstrates that the effect of Tat on transcription elongation requires P-TEFb and suggests that the enhancement of transcriptional processivity by Tat is attributable to enhanced function of P-TEFb on the HIV-1 LTR.
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PMID:Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. 933 25

Activating protein-1 (AP-1) binding TPA responsive elements (TRE) are located downstream of the transcription initiation site in the U5 region of the HIV-1 long terminal repeat (LTR). These downstream sequence elements, termed DSE, can bind both AP-1 and CREB/ATF transcription factors. Recently, we demonstrated that the DSE are also cAMP-responsive elements (CRE), since they mediated activation signals elicited by cholera toxin (Ctx), a potent activator of the cAMP-dependent protein kinase A (PKA) signal transduction pathway. In the present study, we demonstrate that the HIV-1 DSE can mediate the transcriptional synergy elicited by the combination of Ctx and TNFalpha. Ctx combined with TNFalpha or IL-1beta to produce a synergistic increase in p24 antigen production in U1 promonocytic cells. Transfection studies of LTR reporter constructs indicated that mutation of the DSE sites abrogated the LTR-mediated synergy induced by Ctx and TNFalpha, whereas the synergy induced by Ctx and IL-1beta was unaffected, suggesting TNFalpha and IL-1beta cooperate differently with the cAMP/PKA activation pathway to induce HIV-1 expression in U1 cells. Because the DSE are also TRE sites, we assessed the effect of the agonist combinations on AP-1-dependent transcription. TNFalpha as well as IL-1beta cooperated with Ctx to produce a synergistic activation of AP-1-mediated transcription. These data indicate that the TRE-like cAMP-responsive DSE sites within the 5'-untranslated leader can mediate the transcriptional cooperativity between TNFalpha and the cAMP/PKA pathway. Since the DSE and TRE sites cannot bind CREB/ATF homodimers, we propose a mechanism in which the HIV-1 DSE bind heterodimers composed of both AP-1 and CREB/ATF proteins.
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PMID:TNFalpha cooperates with the protein kinase A pathway to synergistically increase HIV-1 LTR transcription via downstream TRE-like cAMP response elements. 935 53

We have previously identified a cellular protein kinase activity termed TAK that specifically associates with the HIV types 1 and 2 Tat proteins. TAK hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II in vitro in a manner believed to activate transcription [Herrmann, C. H. & Rice, A. P. (1995) J. Virol. 69, 1612-1620]. We show here that the catalytic subunit of TAK is a known human kinase previously named PITALRE, which is a member of the cyclin-dependent family of proteins. We also show that TAK activity is elevated upon activation of peripheral blood mononuclear cells and peripheral blood lymphocytes and upon differentiation of U1 and U937 promonocytic cell lines to macrophages. Therefore, in HIV-infected individuals TAK may be induced in T cells following activation and in macrophages following differentiation, thus contributing to high levels of viral transcription and the escape from latency of transcriptionally silent proviruses.
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PMID:TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. 935 49

The Nef protein of HIV-1 is suggested to play a role in depletion of uninfected CD4+ T cells leading to the development of AIDS. The recombinant soluble Nef protein was shown to bind to cell surfaces of various murine lymphoid cell lines, including T and B lymphocytes, mastocytoma cells and macrophages. Cross-linking of the cell-bound Nef protein with anti-Nef antibodies induced apoptotic cytolysis of the cells. Although primary lymphocytes from young mice resisted Nef binding and Nef-induced cytolysis, treatment of the cells with concanavalin A or phytohemagglutinin made them susceptible to these activities, indicating that cellular activation is required for the apoptosis. The Nef-induced apoptosis also occurred with murine cells not expressing CD95 (Fas). These findings were quite similar to those obtained for human blood cells, suggesting that the mouse is applicable for analysis of Nef activities. The Nef-induced apoptosis was efficiently suppressed by serine/threonine protein kinase inhibitors, H7, fasudil hydrochloride and M3, which did not inhibit CD95 (Fas)-mediated apoptosis. On the other hand, bisindolylmaleimide, a protein kinase C inhibitor which inhibits CD95 (Fas)-mediated apoptosis, did not affect Nef-induced apoptosis. These results suggest that the Nef-induced apoptosis of murine cells involved a serine/threonine protein kinase-dependent signal transduction pathway distinct from the CD95 (Fas)-mediated system.
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PMID:Nef protein of HIV-1 induces apoptotic cytolysis of murine lymphoid cells independently of CD95 (Fas) and its suppression by serine/threonine protein kinase inhibitors. 939 75

Leucine-rich nuclear export signals (NESs) are recognized by the NES receptor exportin 1 and are central to the export of multiple shuttling proteins and RNAs. The export of messenger RNA in vertebrates was, however, thought to occur by a different pathway, because inhibition by injection of a synthetic Rev NES conjugate could not be demonstrated. Here we find that peptide conjugates composed of the NES of either protein kinase A inhibitor protein (PKI) or the HIV-1 Rev protein, when coupled to human serum albumin, are potent inhibitors of mRNA and small nuclear RNA export. These results provide direct evidence that mRNA export in vertebrates depends on interactions between an NES and its cognate NES receptors. PKI NES conjugates are significantly more efficient at inhibiting RNA export than are REV NES conjugates, indicating that different NESs may have different abilities to promote protein and RNA export. Surprisingly, an expected control conjugate containing the mutant Rev NES sequence M10 strongly inhibited the export of intronless dihydrofolate reductase mRNA. Nuclear injection of NES peptide conjugates led to mislocalization to the nucleus of 10-20% of the cytoplasmic Ran GTPase-binding protein (RanBP1) indicating that RanBP1 shuttles between the nucleus and the cytoplasm via an NES pathway. These results demonstrate that in vertebrates the export of mRNA, like that of small nuclear RNA, 5S rRNA, and transport factors such as RanBP1, employs NES-mediated molecular machinery.
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PMID:Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates. 940 23

Although the molecular mechanisms by which the HIV-1 triggers either T cell activation, anergy, or apoptosis remain poorly understood, it is well established that the interaction of HIV-1 envelope glycoproteins with cell surface CD4 delivers signals to the target cell, resulting in activation of transcription factors such as NF-kappa B and AP-1. In this study, we report the first evidence indicating that kinases MEK-1 (MAP kinase/Erk kinase) and ERK-1 (extracellular signal-regulated kinase) act as intermediates in the cascade of events that regulate NF-kappa B and AP-1 activation upon HIV-1 binding to cell surface CD4. We found that CEM cells transfected with dominant negative forms of MEK-1 or ERK-1 do not display NF-kappa B activation after HIV-1 binding to CD4. In contrast, NF-kappa B activation was observed in these cells after PMA stimulation. Although the different cell lines studied expressed similar amounts of CD4 and p56(lck), HIV-1 replication and HIV-1-induced apoptosis were slightly delayed in cells expressing dominant negative forms of MEK-1 or ERK-1 compared with parental CEM cells and cells expressing a constitutively active mutant form of MEK-1 or wild-type ERK-1. In light of recently published data, we propose that a positive signal initiated following oligomerization of CD4 by the virus is likely to involve a recruitment of active forms of p56(lck), Raf-1, MEK-1, and ERK-1, before AP-1 and NF-kappa B activation.
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PMID:Involvement of extracellular signal-regulated kinase module in HIV-mediated CD4 signals controlling activation of nuclear factor-kappa B and AP-1 transcription factors. 946 49

The Nef protein of HIV-1 binds to and induces apoptotic cytolysis of uninfected but activated human peripheral blood mononuclear cells (PBMC) and various cell line cells derived from CD4+ T, CD8+ T and B lymphocytes, macrophages, and neutrophils. The Nef-induced apoptosis also occurs with blood cells not expressing CD95 (Fas). The Nef-induced apoptosis as well as Fas-mediated apoptosis was inhibited by acetyl-Try-Val-Ala-Asp-CHO, an IL-1beta converting enzyme (ICE) inhibitor. On the other hand, serine/threonine protein kinase (PK) inhibitors, H-7, fasudil hydrochloride and M3, inhibited the Nef-induced apoptosis, and not the Fas-mediated one, without affecting the cell-binding activity of Nef and Nef-binding capacity of the activated cells. Preincubation of the cells with the drugs before being bound by Nef was required for the inhibition of apoptosis. These results suggest that the PK inhibitors specifically act on a cellular protein involved in the upper stream of signal transduction pathway of the Nef-induced apoptosis, which is different from the Fas-mediated pathway but meets it upstream of ICE. In addition, the drugs suppressed the cellular activation-associated cell surface expression of a putative Nef-binding protein in PBMC, although they had no influence on its expression in cell line cells. These findings suggest the feasibility of clinical use of the PK inhibitors to prevent the development of AIDS by inhibiting the Nef-induced apoptosis of uninfected blood cells.
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PMID:Inhibition of HIV-1 Nef-induced apoptosis of uninfected human blood cells by serine/threonine protein kinase inhibitors, fasudil hydrochloride and M3. 949 17

We have recently demonstrated that the parasite Leishmania donovani and its surface molecule, lipophosphoglycan (LPG), can activate HIV-1 replication in monocytoid cells. Our present interest was to determine whether LPG could also up-regulate HIV-1 transcription in T cells. Using a CD4-positive human lymphoid T cell line (1G5) containing a stably integrated HIV-1 long terminal repeat (LTR)-luciferase construct, we found that LPG is a potent inducer of HIV-1 LTR activity. Treatment of 1G5 cells with signaling antagonists revealed that protein tyrosine kinase- and protein kinase A-dependent pathways were actively participating in the LPG-induced enhancement of HIV-1 LTR-driven activity. Transfection of Jurkat E6.1 cells with plasmids containing wild-type and nuclear factor-kappaB (NF-kappaB)-mutated HIV-1 LTR-luciferase constructs has suggested a role for NF-kappaB binding sites in the LPG-mediated induction of HIV-1 LTR activity. An LPG-induced binding factor specific to the NF-kappaB consensus sequences could be observed using electrophoretic mobility shift assay. Finally, transfection experiments performed with a vector containing HIV-1 kappaB binding sites only showed similar LPG-mediated induction, which was abrogated by sodium salicylate, a known NF-kappaB inhibitor. We thus demonstrate that the LPG-mediated induction of HIV-1 LTR activity in T cells involves several second messengers culminating in activation of HIV-1 LTR-driven transcription via NF-kappaB-binding consensus sequences. In conclusion, these results reinforce the idea that L. donovani is a putative cofactor in HIV-1 pathogenesis.
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PMID:The lipophosphoglycan of Leishmania donovani up-regulates HIV-1 transcription in T cells through the nuclear factor-kappaB elements. 951 Jan 91


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