Regulation of Human Immunodeficiency Virus Type 1 Gene Expression by Clade-Specific Tat Proteins

Desfosses, Yan; Solis, Mayra; Sun, Qiang; Grandvaux, Nathalie; Lint, Carine Van; Burny, Arsène; Gatignol, Anne; Wainberg, Mark A.; Lin, Rongtuan; Hiscott, John

doi:10.1128/jvi.79.14.9180-9191.2005

Cited by 39 publications

(54 citation statements)

References 79 publications

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“…We also observed that at all concentrations tested, there was no significant difference between the three variants except at 400 nM, the highest concentration tested where both subtype C Tat proteins had a higher activity (data not shown). This difference agrees with previously published data using different cell lines (28,44,57,66 (Fig. 1B) and Tat 96Bw (data not shown) elicited a transient increase in [Ca 2ϩ ] i in monocytes that returned to baseline 1 minute after the initial flux.…”

Section: Resultssupporting

confidence: 82%

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Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

Campbell

Watkins

Singh

et al. 2007

J Virol

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Over 50% of all human immunodeficiency virus type 1 (HIV-1) infections worldwide are caused by subtype C strains, yet most research to date focuses on subtype B, the subtype most commonly found in North America and Europe. The HIV-1 trans-acting regulatory protein (Tat) is essential for regulating productive replication of HIV-1. Tat is secreted by HIV-infected cells and alters several functions of uninfected bystander cells. One such function is that, by acting at the cell membrane, subtype B Tat stimulates the production of tumor necrosis factor (TNF) and chemokine (C-C motif) ligand 2 (CCL2) from human monocytes and can act as a chemoattractant. In this study, we show that the mutation of a cysteine to a serine at residue 31 of Tat commonly found in subtype C variants significantly inhibits the abilities of the protein to bind to chemokine (C-C motif) receptor 2 (CCR2), induce intracellular calcium flux, stimulate TNF and CCL2 production, and inhibit its chemoattractant properties. We also show that TNF is important in mediating some effects of extracellular Tat. This report therefore demonstrates the important functional differences between subtype C and subtype B Tat and highlights the need for further investigation into the different strains of HIV-1.

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Section: Resultssupporting

confidence: 82%

“…However, recent research has shown that the different genetic subtypes and recombinant forms of HIV-1 have biological differences with respect to transmission, replication, and disease progression (14,47,74,85). Moreover, different subtypes of Tat have different in vitro effects (17,18,27,28,57,62,66,67,76).…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

Campbell

Watkins

Singh

et al. 2007

J Virol

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“…However, in this trans-activation model, Tat is added as an exogenous protein that must traverse the cell membrane before it can bind the trans-activation responsive element and trans-activate HIV-1 long terminal repeat gene expression. A study using endogenously produced Tat showed that clade C Tat displayed higher affinities for both the trans-activation responsive element and for the positive transcription elongation factor b complex than clade B Tat and displayed a greater trans-activation potential (23). A recent study showed that the serine residues in Tat are phosphorylated by a cyclin-dependent kinase-2 mechanism and that this phosphorylation is important for HIV-1 transcription and the activation of integrated HIV-1 provirus (47).…”

Section: Discussionmentioning

confidence: 99%

“…Tat 93In is typical of clade C isolated, in that it possesses a C31S substitution in the cysteine-rich region (28). Of the seven highly conserved cysteines in Tat, only substitutions of Cys 31 do not affect its trans-activational ability (21,23,24,29).…”

Section: Tat Induces Il-10 In a Time-and Dose-dependent Manner Inmentioning

confidence: 99%

“…This motif is essential for the induction of a Ca 2ϩ flux in, and chemotaxis of, monocytes and the induction of inflammatory cytokines and chemokines. Conversely, disruption of this motif actually increases its trans-activational activity (6,7,22,23). To date, no study has assessed the capacity of different full length HIV-1 Tat clades to induce IL-10 production in monocytes.…”

mentioning

confidence: 99%

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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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HIV Tat protein: Is Tat‐C much trickier than Tat‐B?

Johri

Sharma

Singh

2015

Journal of Medical Virology

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Out of various subtypes of human immunodeficiency virus type 1 (HIV-1), subtype B and C cause most of the infections worldwide. Clade specific differences have been reported in differences in clinical picture of HIV pathogenesis. Transcription of the HIV-1 genome is regulated by the interaction of HIV Tat protein to the trans-activation response (TAR) element. The differential binding of clade B and C Tat proteins to TAR and differences in activation of NF-κB cascade leading to differential transactivation capacity and cytokine expression has been examined in this study. More stable Tat-TAR complex formation by Tat-C revealed by EMSA and higher TNF-α expression shown by Tat-C compared to Tat-B leads to higher NF-κB activation, which may be plausible cause for higher transactivation by Tat-C as obtained by FACS analysis. This comparative study would be helpful in understanding the basic mechanism of clade specific Tat protein differences and their functional relationships.

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Regulation of Human Immunodeficiency Virus Type 1 Gene Expression by Clade-Specific Tat Proteins

Cited by 39 publications

References 79 publications

Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

Human Immunodeficiency Virus Type 1 Subtype C Tat Fails To Induce Intracellular Calcium Flux and Induces Reduced Tumor Necrosis Factor Production from Monocytes

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

HIV Tat protein: Is Tat‐C much trickier than Tat‐B?

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