scholarly journals Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor

2019 ◽  
Vol 93 (24) ◽  
Author(s):  
Vânia Passos ◽  
Thomas Zillinger ◽  
Nicoletta Casartelli ◽  
Amelie S. Wachs ◽  
Shuting Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Subcellular Localization ◽  
Transmembrane Protein ◽  
Type I ◽  
Accessory Gene ◽  
Protein Levels ◽  
Specificity And Sensitivity ◽  
Hiv 1

ABSTRACT When expressed in virus-producing cells, the cellular multipass transmembrane protein SERINC5 reduces the infectivity of HIV-1 particles and is counteracted by HIV-1 Nef. Due to the unavailability of an antibody of sufficient specificity and sensitivity, investigation of SERINC5 protein expression and subcellular localization has been limited to heterologously expressed SERINC5. We generated, via CRISPR/Cas9-assisted gene editing, Jurkat T-cell clones expressing endogenous SERINC5 bearing an extracellularly exposed hemagglutinin (HA) epitope [Jurkat SERINC5(iHA knock-in) T cells]. This modification enabled quantification of endogenous SERINC5 protein levels and demonstrated a predominant localization in lipid rafts. Interferon alpha (IFN-α) treatment enhanced cell surface levels of SERINC5 in a ruxolitinib-sensitive manner in the absence of modulation of mRNA and protein quantities. Parental and SERINC5(iHA knock-in) T cells shared the ability to produce infectious wild-type HIV-1 but not an HIV-1 Δnef mutant. SERINC5-imposed reduction of infectivity involved a modest reduction of virus fusogenicity. An association of endogenous SERINC5 protein with HIV-1 Δnef virions was consistently detectable as a 35-kDa species, as opposed to heterologous SERINC5, which presented as a 51-kDa species. Nef-mediated functional counteraction did not correlate with virion exclusion of SERINC5, arguing for the existence of additional counteractive mechanisms of Nef that act on virus-associated SERINC5. In HIV-1-infected cells, Nef triggered the internalization of SERINC5 in the absence of detectable changes of steady-state protein levels. These findings establish new properties of endogenous SERINC5 expression and subcellular localization, challenge existing concepts of HIV-1 Nef-mediated antagonism of SERINC5, and uncover an unprecedented role of IFN-α in modulating SERINC5 through accumulation at the cell surface. IMPORTANCE SERINC5 is the long-searched-for antiviral factor that is counteracted by the HIV-1 accessory gene product Nef. Here, we engineered, via CRISPR/Cas9 technology, T-cell lines that express endogenous SERINC5 alleles tagged with a knocked-in HA epitope. This genetic modification enabled us to study basic properties of endogenous SERINC5 and to verify proposed mechanisms of HIV-1 Nef-mediated counteraction of SERINC5. Using this unique resource, we identified the susceptibility of endogenous SERINC5 protein to posttranslational modulation by type I IFNs and suggest uncoupling of Nef-mediated functional antagonism from SERINC5 exclusion from virions.

scholarly journals Human Immunodeficiency Virus Type 1 Derived from Cocultures of Immature Dendritic Cells with Autologous T Cells Carries T-Cell-Specific Molecules on Its Surface and Is Highly Infectious

1999 ◽  
Vol 73 (4) ◽  
pp. 3449-3454 ◽  
Author(s):  
Ines Frank ◽  
Laco Kacani ◽  
Heribert Stoiber ◽  
Hella Stössel ◽  
Martin Spruth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Surface ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT During the budding process, human immunodeficiency virus type 1 (HIV-1) acquires cell surface molecules; thus, the viral surface of HIV-1 reflects the antigenic pattern of the host cell. To determine the source of HIV-1 released from cocultures of dendritic cells (DC) with T cells, immature DC (imDC), mature DC (mDC), T cells, and their cocultures were infected with different HIV-1 isolates. The macrophage-tropic HIV-1 isolate Ba-L allowed viral replication in both imDC and mDC, whereas the T-cell-line-tropic primary isolate PI21 replicated in mDC only. By a virus capture assay, HIV-1 was shown to carry a T-cell- or DC-specific cell surface pattern after production by T cells or DC, respectively. Upon cocultivation of HIV-1-pulsed DC with T cells, HIV-1 exclusively displayed a typical T-cell pattern. Additionally, functional analysis revealed that HIV-1 released from imDC–T-cell cocultures was more infectious than HIV-1 derived from mDC–T-cell cocultures and from cultures of DC, T cells, or peripheral blood mononuclear cells alone. Therefore, we conclude that the interaction of HIV-1-pulsed imDC with T cells in vivo might generate highly infectious virus which primarily originates from T cells.

scholarly journals Activation of a dendritic cell–T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells

2008 ◽  
Vol 205 (12) ◽  
pp. 2717-2725 ◽  
Author(s):  
Matthieu Perreau ◽  
Giuseppe Pantaleo ◽  
Eric J. Kremer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Complexes ◽  
Vaccine Trial ◽  
Type I Interferons ◽  
Type I ◽  
Cell Axis ◽  
Vector Vaccine ◽  
Hiv 1

The STEP HIV vaccine trial, which evaluated a replication-defective adenovirus type 5 (Ad5) vector vaccine, was recently stopped. The reasons for this included lack of efficacy of the vaccine and a twofold increase in the incidence of HIV acquisition among vaccinated recipients with increased Ad5-neutralizing antibody titers compared with placebo recipients. To model the events that might be occurring in vivo, the effect on dendritic cells (DCs) of Ad5 vector alone or treated with neutralizing antiserum (Ad5 immune complexes [IC]) was compared. Ad5 IC induced more notable DC maturation, as indicated by increased CD86 expression, decreased endocytosis, and production of tumor necrosis factor and type I interferons. We found that DC stimulation by Ad5 IC was mediated by the Fcγ receptor IIa and Toll-like receptor 9 interactions. DCs treated with Ad5 IC also induced significantly higher stimulation of Ad5-specific CD8 T cells equipped with cytolytic machinery. In contrast to Ad5 vectors alone, Ad5 IC caused significantly enhanced HIV infection in DC–T cell cocultures. The present results indicate that Ad5 IC activates a DC–T cell axis that, together with the possible persistence of the Ad5 vaccine in seropositive individuals, may set up a permissive environment for HIV-1 infection, which could account for the increased acquisition of HIV-1 infection among Ad5 seropositive vaccine recipients.

scholarly journals HIV-1 Induction of Tolerogenic DCs is Mediated by Cellular Interaction with Suppressive T Cells

2021 ◽  
Author(s):  
Cecilia Svanberg ◽  
Sofia Nyström ◽  
Melissa Govender ◽  
Pradyot Bhattacharya ◽  
Karlhans F Che ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Cellular Interaction ◽  
Type I ◽  
Dependent Manner ◽  
Hiv Exposed ◽  
Hiv 1 ◽  
Tolerogenic Dcs

AbstractHIV-1 infection gives rise to a multilayered immune impairment in most infected individuals. The crosstalk between Dendritic cells and T cells plays an important part in the induction of immune responses. The chronic presence of human immunodeficiency virus (HIV)-1 during the dendritic cells (DCs) priming and activation of T cells promotes the expansion of suppressor cells in a contact dependent manner. The mechanism behind the T cell side of this HIV induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs in this setting.Here we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The DCs in the HIV exposed DC-T cell coculture obtained a more tolerogenic/suppressive phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by their cellular interaction with T cells. The transcriptomic analysis showed a clear type I IFN response profile as well as an activation of pathways involved in T cell exhaustion.Taken together, our data indicate that the prolonged and strong IFN type I signaling induced by the presence of HIV during DC-T cell cross talk could play an important role in the induction of the tolerogenic DCs and suppressed immune response.

scholarly journals Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins

Virology ◽  
2018 ◽  
Vol 516 ◽  
pp. 21-29 ◽  
Author(s):  
Mingce Zhang ◽  
Tanya O. Robinson ◽  
Alexandra Duverger ◽  
Olaf Kutsch ◽  
Sonya L. Heath ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cd4 T Cells ◽  
Regulatory Proteins ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Hiv 1

scholarly journals CD4+CD73+ T cells are associated with lower T-cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression

AIDS ◽  
2013 ◽  
Vol 27 (10) ◽  
pp. 1545-1555 ◽  
Author(s):  
Patrick J. Schuler ◽  
Bernard J.C. Macatangay ◽  
Zenichiro Saze ◽  
Edwin K. Jackson ◽  
Sharon A. Riddler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Suppression ◽  
C Reactive Protein ◽  
Protein Levels ◽  
Reactive Protein ◽  
Hiv 1

scholarly journals The B-Oligomer of Pertussis Toxin Deactivates Cc Chemokine Receptor 5 and Blocks Entry of M-Tropic HIV-1 Strains

1999 ◽  
Vol 190 (5) ◽  
pp. 597-606 ◽  
Author(s):  
Massimo Alfano ◽  
Helena Schmidtmayerova ◽  
Carol-Ann Amella ◽  
Tatiana Pushkarsky ◽  
Michael Bukrinsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Pertussis Toxin ◽  
Chemokine Receptor ◽  
Viral Envelope ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Peripheral Blood Mononuclear ◽  
Hiv 1

Infection of target cells by HIV-1 requires initial binding interactions between the viral envelope glycoprotein gp120, the cell surface protein CD4, and one of the members of the seven-transmembrane G protein–coupled chemokine receptor family. Most primary isolates (R5 strains) use chemokine receptor CCR5, but some primary syncytium-inducing, as well as T cell line–adapted, strains (X4 strains) use the CXCR4 receptor. Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive Gi proteins and is not required for HIV-1 entry. Here, we show that the PTX holotoxin as well as its binding subunit, B-oligomer, which lacks Gi-inhibitory activity, blocked entry of R5 but not X4 strains into primary T lymphocytes. Interestingly, B-oligomer inhibited virus production by peripheral blood mononuclear cell cultures infected with either R5 or X4 strains, indicating that it can affect HIV-1 replication at both entry and post-entry levels. T cells treated with B-oligomer did not initiate signal transduction in response to macrophage inflammatory protein (MIP)-1β or RANTES (regulated upon activation, normal T cell expressed and secreted); however, cell surface expression of CCR5 and binding of MIP-1β or HIV-1 to such cells were not impaired. The inhibitory effect of B-oligomer on signaling from CCR5 and on entry of R5 HIV-1 strains was reversed by protein kinase C (PKC) inhibitors, indicating that B-oligomer activity is mediated by signaling events that involve PKC. B-oligomer also blocked cocapping of CCR5 and CD4 induced by R5 HIV-1 in primary T cells, but did not affect cocapping of CXCR4 and CD4 after inoculation of the cultures with X4 HIV-1. These results suggest that the B-oligomer of PTX cross-deactivates CCR5 to impair its function as a coreceptor for HIV-1.

Regulation of the cell-surface expression of an HTLV-I binding protein in human T cells during immune activation

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3085-3092 ◽  
Author(s):  
Manisha D. Nath ◽  
Francis W. Ruscetti ◽  
Cari Petrow-Sadowski ◽  
Kathryn S. Jones
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Lines ◽  
Cd4 T Cells ◽  
Binding Protein ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Type I ◽  
Primary Cells

AbstractLittle is known about the requirements for human T-cell leukemia virus type I (HTLV-I) entry, including the identity of the cellular receptor(s). Recently, we have generated an HTLV-I surface glycoprotein (SU) immunoadhesin, HTSU-IgG, which binds specifically to cell-surface protein(s) critical for HTLV-I–mediated entry in cell lines. Here, expression of the HTLV-I SU binding protein on primary cells of the immune system was examined. The immunoadhesin specifically bound to adult T cells, B cells, NK cells, and macrophages. Cell stimulation dramatically increased the amount of binding, with the highest levels of binding on CD4+ and CD8+ T cells. Naive (CD45RAhigh, CD62Lhigh) CD4+ T cells derived from cord blood cells, in contrast to other primary cells and all cell lines examined, bound no detectable HTLV-I SU. However, following stimulation, the level of HTSU-IgG binding was rapidly induced (fewer than 6 hours), reaching the level of binding seen on adult CD4+ T cells by 72 hours. In contrast to HTLV-I virions, the soluble HTSU-IgG did not effect T-cell activation or proliferation. When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction, HTSU-IgG inhibited proliferation at less than 1 ng/mL. These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immunobiology of CD4+ T cells.

scholarly journals Absence of cGAS-mediated type I IFN responses in HIV-1–infected T cells

2020 ◽  
Vol 117 (32) ◽  
pp. 19475-19486
Author(s):  
Carina Elsner ◽  
Aparna Ponnurangam ◽  
Julia Kazmierski ◽  
Thomas Zillinger ◽  
Jenny Jansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Plasmid Dna ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
T Cell Lines ◽  
Hiv 1 ◽  
Dependent Type

The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4+T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression ofIFIT1andMX2was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4+T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1ΔUL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4+T cells, plasmid challenge or HSV-1ΔUL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1ΔUL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.

scholarly journals Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics

2007 ◽  
Vol 82 (4) ◽  
pp. 1870-1883 ◽  
Author(s):  
Ahmad R. Sedaghat ◽  
Jennifer German ◽  
Tanya M. Teslovich ◽  
Joseph Cofrancesco ◽  
Chunfa C. Jie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The mechanism of CD4+ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4+ T-cell activation. We assumed that the pathogenic process of excessive CD4+ T-cell activation would be reflected in the transcriptional profiles of activated CD4+ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4+ T cells from untreated HIV-positive (HIV+) individuals are clearly different from those of activated CD4+ T cells from HIV-negative (HIV−) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4+ T cells of untreated HIV+ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4+ T cells of untreated HIV+ individuals compared to those of HIV− individuals. We confirm these findings by examination of in vivo-activated CD4+ T cells. Taken together, these results suggest that activated CD4+ T cells from untreated HIV+ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4+ T-cell depletion during chronic HIV-1 infection.

Effect of RELT on regulation of the threshold of T-cell activation during sterile inflammation.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 25-25
Author(s):  
Seon-Hee Kim ◽  
Beom K. Choi ◽  
Chungyong Han ◽  
Byoung S. Kwon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Injury ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Sterile Inflammation ◽  
Tumor Growth Rate ◽  
Lymphoid Tissues ◽  
Type I

25 Background: Receptor expressed in lymphoid tissue (RELT) is a type I transmembrane protein, designated TNFRSF19-like, and primarily expressed in lymphoid tissues and immune cells. However, its immunological function has yet to be characterized. Methods: We developed RELT-deficient mice to examine the immunological role of RELT. The RELT–/– mice were exposed to viral and bacterial infection, chemical-induced liver injury, and tumor induction. Results: RELT–/– mice were viable and fertile, and developed normal lymphoid and myeloid cells. RELT transcripts were decreased in T cells and dendritic cells following their activation, and T-cell proliferation was enhanced in the absence of RELT in vitro. Nevertheless, we could not find significant changes in RELT–/– mice infected with virus or bacteria. However, liver injury and inflammation were significantly increased in RELT–/– mice in comparison to RELT+/+ mice after the injection of acetaminophen. Tumor growth rate was also slower in RELT–/– than RELT+/+ mice. Transfer of naïve or activated pmel-1 CD8+ T cells suppressed the growth of B16–F10 tumors and increased host CD8+ tumor-infiltrating cells more efficiently in RELT–/– than in RELT+/+ mice. In particular, naïve pmel-1 CD8+ T cells were present in increased numbers and activated forms in draining lymph nodes of RELT–/– than in RELT+/+ mice, whereas activated pmel-1 CD8+ T cells were not. Conclusions: As RELT–/– mice only showed significant differences in comparison to RELT+/+ mice in pathogen-associated-molecular-pattern-free conditions, these results provide evidence that RELT functions as a negative modulator of T cell responses in a sterile inflammation.

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