scholarly journals The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block

2017 ◽  
Vol 91 (7) ◽  
Author(s):  
Suzannah J. Rihn ◽  
Toshana L. Foster ◽  
Idoia Busnadiego ◽  
Muhamad Afiq Aziz ◽  
Joseph Hughes ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Type I Interferon ◽  
Single Amino Acid ◽  
Envelope Gene ◽  
Type I ◽  
Type Ii ◽  
Antiviral State ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission. IMPORTANCE The human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition.

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.

Structure of the two promoters of the human lck gene: differential accumulation of two classes of lck transcripts in T cells

1989 ◽  
Vol 9 (5) ◽  
pp. 2173-2180
Author(s):  
T Takadera ◽  
S Leung ◽  
A Gernone ◽  
Y Koga ◽  
Y Takihara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Human Peripheral Blood ◽  
Specific Gene ◽  
Type I ◽  
Type Ii ◽  
Carcinoma Cell Lines ◽  
Human T Cell

The human T-cell- or lymphocyte-specific gene, lck, encodes a tyrosine kinase and is a member of the src family. In this report we demonstrate that there are two classes of human lck transcripts (types I and II), containing different 5'-untranslated regions, which are expressed from two distinct promoters. No apparent sequence similarity was observed between the 5'-flanking regions of the two promoters. The expression of lck in human T-cell leukemia and carcinoma cell lines and in human peripheral blood T lymphocytes was examined by S1 nuclease and primer extension mapping and by Northern (RNA) blot analysis of total cellular RNA. The following results were obtained. (i) Two RNA start sites in the downstream promoter were used to generate type I transcripts. (ii) The major human type I start site has not been described for the mouse. (iii) At least five RNA start sites in the upstream promoter were used to generate type II transcripts. (iv) In T cells and in two colon carcinoma cell lines, type II transcripts were present in higher amounts than type I transcripts. (v) In T cells treated with phytohemagglutinin, tetradecanoylphorbol acetate, and cyclosporin A, the modulation of lck expression was associated primarily with changes in levels of type II transcripts. The above results suggest that the two human lck promoters are utilized differentially and may be regulated independently during certain physiological states.

scholarly journals Type I Interferon Is a Powerful Inhibitor of in Vivo HIV-1 Infection and Preserves Human CD4+ T Cells from Virus-Induced Depletion in SCID Mice Transplanted with Human Cells

Virology ◽  
1999 ◽  
Vol 263 (1) ◽  
pp. 78-88 ◽  
Author(s):  
Caterina Lapenta ◽  
Stefano M. Santini ◽  
Enrico Proietti ◽  
Paola Rizza ◽  
Mariantonia Logozzi ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Type I Interferon ◽  
Human Cells ◽  
Scid Mice ◽  
Type I ◽  
Hiv 1

P.1.04 Impacts of type I interferons (IFN-α andIFN-τ) and type II interferon (IFN-γ) on the kynurenine pathway in human uninfected or HIV-1 infected macrophages

2005 ◽  
Vol 15 ◽  
pp. S6
Author(s):  
B. Manéglier ◽  
C. Rogez-Kreuz ◽  
O. Spreux-Varoquaux ◽  
N. Dereuddre-Bosquet ◽  
J. Marlal ◽  
...  
Keyword(s):  
Kynurenine Pathway ◽  
Type I Interferons ◽  
Type I ◽  
Type Ii ◽  
Ifn Γ ◽  
Hiv 1

scholarly journals Structure of the two promoters of the human lck gene: differential accumulation of two classes of lck transcripts in T cells.

1989 ◽  
Vol 9 (5) ◽  
pp. 2173-2180 ◽  
Author(s):  
T Takadera ◽  
S Leung ◽  
A Gernone ◽  
Y Koga ◽  
Y Takihara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Human Peripheral Blood ◽  
Specific Gene ◽  
Type I ◽  
Type Ii ◽  
Carcinoma Cell Lines ◽  
Human T Cell

The human T-cell- or lymphocyte-specific gene, lck, encodes a tyrosine kinase and is a member of the src family. In this report we demonstrate that there are two classes of human lck transcripts (types I and II), containing different 5'-untranslated regions, which are expressed from two distinct promoters. No apparent sequence similarity was observed between the 5'-flanking regions of the two promoters. The expression of lck in human T-cell leukemia and carcinoma cell lines and in human peripheral blood T lymphocytes was examined by S1 nuclease and primer extension mapping and by Northern (RNA) blot analysis of total cellular RNA. The following results were obtained. (i) Two RNA start sites in the downstream promoter were used to generate type I transcripts. (ii) The major human type I start site has not been described for the mouse. (iii) At least five RNA start sites in the upstream promoter were used to generate type II transcripts. (iv) In T cells and in two colon carcinoma cell lines, type II transcripts were present in higher amounts than type I transcripts. (v) In T cells treated with phytohemagglutinin, tetradecanoylphorbol acetate, and cyclosporin A, the modulation of lck expression was associated primarily with changes in levels of type II transcripts. The above results suggest that the two human lck promoters are utilized differentially and may be regulated independently during certain physiological states.

Identification of Functional HLA-A*01:01–Restricted Epstein-Barr Latent Membrane Protein 2–Specific T-Cell Receptors

2020 ◽  
Author(s):  
Wesley Huisman ◽  
Ilse Gille ◽  
Lieve E van der Maarel ◽  
Lois Hageman ◽  
Laura T Morton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
T Cell Receptors ◽  
Genetically Engineered ◽  
Type Ii ◽  
Cell Receptors ◽  
Tetramer Binding ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background Adoptive transfer of genetically engineered T cells expressing antigen-specific T-cell receptors (TCRs) is an appealing therapeutic approach for Epstein-Barr virus (EBV)–associated malignancies of latency type II/III that express EBV antigens (LMP1/2). Patients who are HLA-A*01:01 positive could benefit from such products, since no T cells recognizing any EBV-derived peptide in this common HLA allele have been found thus far. Methods HLA-A*01:01–restricted EBV-LMP2–specific T cells were isolated using peptide major histocompatibility complex (pMHC) tetramers. Functionality was assessed by production of interferon gamma (IFN-γ) and cytotoxicity when stimulated with EBV-LMP2–expressing cell lines. Functionality of primary T cells transduced with HLA-A*01:01–restricted EBV-LMP2–specific TCRs was optimized by knocking out the endogenous TCRs of primary T cells (∆TCR) using CRISPR-Cas9 technology. Results EBV-LMP2–specific T cells were successfully isolated and their TCRs were characterized. TCR gene transfer in primary T cells resulted in specific pMHC tetramer binding and reactivity against EBV-LMP2–expressing cell lines. The mean fluorescence intensity of pMHC-tetramer binding was increased 1.5–2 fold when the endogenous TCRs of CD8+ T cells was knocked out. CD8+/∆TCR T cells modified to express EBV-LMP2–specific TCRs showed IFN-γ secretion and cytotoxicity toward EBV-LMP2–expressing malignant cell lines. Conclusions We isolated the first functional HLA-A*01:01–restricted EBV-LMP2–specific T-cell populations and TCRs, which can potentially be used in future TCR gene therapy to treat EBV-associated latency type II/III malignancies.

scholarly journals Prothymosin α Variants Isolated From CD8+ T Cells and Cervicovaginal Fluid Suppress HIV-1 Replication Through Type I Interferon Induction

2014 ◽  
Vol 211 (9) ◽  
pp. 1467-1475 ◽  
Author(s):  
Avelino Teixeira ◽  
Benjamin Yen ◽  
Gabriele Luca Gusella ◽  
Albert G. Thomas ◽  
Michael P. Mullen ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Type I ◽  
Prothymosin Α ◽  
Interferon Induction ◽  
Hiv 1 ◽  
Cervicovaginal Fluid

scholarly journals Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Hisashi Akiyama ◽  
Nora-Guadalupe Pina Ramirez ◽  
Gregory Gibson ◽  
Christopher Kline ◽  
Simon Watkins ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Myeloid Cells ◽  
Cell Types ◽  
Productive Infection ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral State ◽  
Hiv 1

ABSTRACT A hallmark of human immunodeficiency virus type 1 (HIV-1) infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4+ T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gag and CD169, suggesting productive infection of CD169+ myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+ T cells was robustly decreased, initiation of infection in trans via coculture with CD169+ IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state. IMPORTANCE HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell types in vitro, HIV-1 can replicate in vivo via mechanisms that have remained unclear. In this study, we tested the hypothesis that CD169, a type I IFN-inducible HIV-1 attachment factor, offsets antiviral effects of type I IFN. Infection of HIV-1 was rescued in IFN-α-treated myeloid cells via upregulation of CD169 and a subsequent increase in CD169-dependent virus entry. Furthermore, extensive colocalization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169+ cells in vivo. Treatment of dendritic cell (DC)-T cell cocultures with IFN-α upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4+ T cells in trans, suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions.

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