Identification of a Novel Domain of HIV Tat Involved in Monocyte Chemotaxis

Albini, Adriana; Benelli, Roberto; Giunciuglio, Daniela; Cai, Tania; Mariani, Giuliano; Ferrini, Silvano; Noonan, Douglas M.

doi:10.1074/jbc.273.26.15895

Cited by 117 publications

(97 citation statements)

References 40 publications

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“…This study monitored the intracellular calcium flux for 30 min using microspectrofluorimetry with images captured every 5 s, while our study observed the intracellular calcium flux over 3 min using real time flow cytometry. Using this method, we detected a rapid and transient calcium flux following B Tat treatment that is consistent with other studies using similar methods (5,9,30,48) that was possibly missed using a time-lapse method. Our results also show that Ca L and PI3K inhibitors reduce the ability of clade B Tat to induce IL-10 production in monocytes.…”

Section: Discussionsupporting

confidence: 77%

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Wong

Campbell

Spector

2010

Journal of Biological Chemistry

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The clade B human immunodeficiency virus, type 1 (HIV-1) Tat (trans-acting regulatory protein) induces interleukin-10 (IL-10) production in monocytes. IL-10, an anti-inflammatory cytokine, down-regulates proinflammatory cytokines and suppresses the immune response, leading to a rapid progression from HIV-1 infection to AIDS. Nine clades of HIV-1 are responsible for the majority of infections worldwide. Recent studies demonstrate that different HIV-1 clades have biological differences in relation to transmission, replication, and disease progression. In this study, we show that the cysteine to serine mutation at position 31, found in >90% of HIV-1 clade C Tat proteins, results in a marked decrease in IL-10 production in monocytes compared with clade B Tat. Additionally, the C31S mutation found in C Tat is responsible for the inability of these Tat proteins to produce high IL-10 levels in monocytes due to its inability to induce intracellular calcium flux through L-type calcium channels. Moreover, we show that p38␣/p38␤ and phosphoinositide 3-kinase are crucial to Tat-induced IL-10 production. These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression.The human immunodeficiency virus type 1 (HIV-1) 3 transacting regulatory protein (Tat) is an 86 -101-residue protein involved in initiating viral transcription and RNA chain elongation. In addition to its primary role as a transcriptional activator of viral gene expression, Tat is actively released from unruptured, HIV-1-infected cells and is detectable in ex vivo culture supernatants and in the serum of HIV-1 infected individuals (1, 2). Most exogenous Tat studies use a truncated 86-residue HIV-1 clade B Tat with few studies examining the functions of other clades or isotypes (3). However, these studies have shown that exogenous B Tat induces the production of cytokines, such as tumor necrosis factor, chemokine (C-C motif) ligand 2 (CCL2), interleukin-6 (IL-6), and interleukin-10 (IL-10) from monocytes and macrophages (4 -9).The expression of IL-10-specific mRNA and the production of IL-10 are both increased in HIV-1-infected individuals (10 -12). IL-10 is an anti-inflammatory cytokine produced by a wide variety of cells including monocytes, macrophages, T cells, natural killer cells, and B cells (13) that down-regulates major histocompatibility complex class II (13) and inhibits T cell proliferation while reducing the production of proinflammatory cytokines. Elevated IL-10 levels are found in individuals with rapid progression to AIDS (14 -16), and individuals with higher plasma levels of IL-10 have more severely compromised T helper cell function (14 -16) combined with lower T helper cell counts (17). Interestingly, in samples from patients chronically infected with HIV, blocking the IL-10/IL-10 receptor pathway in vitro using specific antibodies enhanced CD4 ϩ T cell responses (14 -16). Therefore, maintaining low levels of IL-10 may slow HIV-1 disease progression.Recen...

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Section: Discussionsupporting

confidence: 77%

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Wong

Campbell

Spector

2010

Journal of Biological Chemistry

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“…Cell migration assays were conducted on SH-SY5Y, ACN, and LA1-5S cells in microchambers (NeuroProbes Gaithersburg) as previously described (20). Cells were extensively washed with PBS, resuspended in serum-free medium, and placed in the upper compartment.…”

Section: Neuroblastoma Cell Migration Assaymentioning

confidence: 99%

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

Grosso

Coco

Scaruffi

et al. 2011

Molecular Cancer Research

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Neuroblastoma is a stroma-poor (SP) aggressive pediatric cancer belonging to neuroblastic tumors, also including ganglioneuroblastoma and ganglioneuroma, two stroma-rich (SR) less aggressive tumors. Our previous gene-expression profiling analysis showed a different CXCL13 mRNA expression between SP and SR tumors. Therefore, we studied 13 SP and 13 SR tumors by reverse transcription quantitative real-time PCR (RT-qPCR) and we found that CXCR5b was more expressed in SP than in SR and CXCL13 was predominantly expressed in SR tumors. Then, we isolated neuroblastic and Schwannian stromal cells by laser capture microdissection and we found that malignant neuroblasts express CXCR5b mRNA, whereas Schwannian stromal cells express CXCL13. Immunohistochemistry confirmed that stroma expresses CXCL13 but not CXCR5. To better understand the role of CXCL13 and CXCR5 in neuroblastic tumors we studied 11 neuroblastoma cell lines and we detected a heterogeneous expression of CXCL13 and CXCR5b. Interestingly, we found that only CXCR5b splice variant was expressed in both tumors and neuroblastoma lines, whereas CXCR5a was never detected. Moreover, we found that neuroblastoma cells expressing CXCR5 receptor migrate toward a source of recombinant CXCL13. Lastly, neuroblastoma cells induced to glial cell differentiation expressed CXCL13 mRNA and protein. The chemokine released in the culture medium was able to stimulate chemotaxis of LA1-5S neuroblastoma cells. Collectively, our data suggest that CXCL13 produced by stromal cells may contribute to the generation of an environment in which the malignant neuroblasts are retained, thus limiting the possible development of metastases in patients with SR tumor. Mol Cancer Res; 9(7); 815-23. '2011 AACR.

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“…In fact, a preponderance of reports has unequivocally established that Tat possesses a unique biological activity that alters the function of monocytes, dendritic cells (DCs), and CD4 ϩ and CD8 ϩ T cells in vitro (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In addition, detectable levels of extracellular Tat are found in culture supernatants from cells infected with HIV-1 (20)(21)(22), and Tat is efficiently taken up by a variety of cells (21)(22)(23)(24)(25).…”

mentioning

confidence: 99%

A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice

Agwale

Shata²,

Reitz³

et al. 2002

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

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The rational design of new therapies against HIV-1 necessitates an improved understanding of the mechanisms underlying the production of ineffective immune responses to HIV-1 in most infected individuals. This report shows that the CD8 ؉ T cell responses to gp120 were greatly diminished in mice vaccinated with a bicistronic gp120-Tat DNA vaccine, compared with those induced by a DNA vaccine encoding gp120 alone. The CD8 ؉ T cell responses induced by the latter included strong gp120-specific IFN-␥ secretion and protective antiviral immunity against challenge by a vacciniaenv pseudotype. The degree to which Tat influenced CD8 ؉ T cell responses depended on the bioactivity of Tat. Thus, a bicistronic DNA vaccine that expresses gp120 and a truncated Tat defective for LTR activation elicited strong IFN-␥ -secreting CD8 ؉ T cell responses to gp120 but conferred only marginal protection against the vaccinia-env challenge. The effect of Tat was completely blocked, however, by immunization with inactivated Tat protein before vaccination with the bicistronic gp120-Tat DNA vaccine.HIV-1 ͉ immune response ͉ CD8 ϩ T cell ͉ regulation

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Identification of a Novel Domain of HIV Tat Involved in Monocyte Chemotaxis

Abstract: Human immunodeficiency virus (HIV)Tat

Cited by 117 publications

References 40 publications

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Differential Induction of Interleukin-10 in Monocytes by HIV-1 Clade B and Clade C Tat Proteins

Role of CXCL13-CXCR5 Crosstalk Between Malignant Neuroblastoma Cells and Schwannian Stromal Cells in Neuroblastic Tumors

A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice

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