scholarly journals Interferon-inducible miR-128 modulates HIV-1 replication by targeting TNPO3 mRNA

2017 ◽  
Author(s):  
Aurore Bochnakian ◽  
Dimitrios G Zisoulis ◽  
Adam Idica ◽  
Anjie Zhen ◽  
Vineet N KewalRamani ◽  
...  
Keyword(s):  
T Cells ◽  
Nuclear Import ◽  
Cd4 T Cells ◽  
Jurkat Cells ◽  
Type I ◽  
Coding Region ◽  
Aids Pandemic ◽  
Mrna And Protein Expression ◽  
Dual Mechanism ◽  
Hiv 1

ABSTRACTThe HIV/AIDS pandemic remains an important threat to human health. We have recently demonstrated that a novel microRNA (miR-128) represses retrotransposon (LINE-1 or L1) by a dual mechanism, by directly targeting the coding region of the L1 RNA and by repressing a required nuclear import factor (TNPO1). We have further determined that miR-128 represses the expression of all three isoforms of TNPO proteins (transportins, TNPO1,-2 and TNPO3). Here, we establish that miR-128 also controls HIV-1 replication by repressing TNPO3. TNPO3 is well established to regulate HIV-1 nuclear import and viral replication. Here, we report that the type I interferon inducible miR-128 directly targets two sites in the TNPO3 mRNA, significantly down-regulating TNPO3 mRNA and protein expression levels. Manipulation of miR-128 levels in HIV target cell lines and in primary human CD4 T-cells by over-expression or knockdown showed that modulation of TNPO3 by miR-128 affects HIV-1 replication but not MLV infection. In addition, we found that miR-128 modulation of HIV-1 replication is reduced with TNPO3-independent HIV-1 virus and in cells depleted of CPSF6, suggesting that miR-128-indued TNPO3 repression is partly required for miR-128-induced inhibition of HIV-1 replication. Finally, challenging miR-modulated Jurkat cells or primary CD4 T-cells with wildtype, replication-competent HIV-1 shows that miR-128 significantly delays spreading infection. Thus, we have established a novel role of miR-128 in anti-viral defense in human cells, inhibiting HIV-1 replication partly by targeting TNPO3.

scholarly journals Interferon-Inducible MicroRNA miR-128 Modulates HIV-1 Replication by Targeting TNPO3 mRNA

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Aurore Bochnakian ◽  
Anjie Zhen ◽  
Dimitrios G. Zisoulis ◽  
Adam Idica ◽  
Vineet N. KewalRamani ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Nuclear Import ◽  
Infection Type ◽  
Jurkat Cells ◽  
Therapeutic Interventions ◽  
Type I Interferons ◽  
Type I ◽  
Coding Region ◽  
Hiv 1

ABSTRACT The HIV/AIDS pandemic remains an important threat to human health. We have recently demonstrated that a novel microRNA (miR), miR-128, represses retrotransposon long interspaced element 1 (L1) by a dual mechanism, namely, by directly targeting the coding region of the L1 RNA and by repressing a required nuclear import factor (TNPO1). We have further determined that miR-128 represses the expression of all three TNPO proteins (transportins TNPO1, TNPO2, and TNPO3). Here, we establish that miR-128 also influences HIV-1 replication by repressing TNPO3, a factor that regulates HIV-1 nuclear import and viral; replication of TNPO3 is well established to regulate HIV-1 nuclear import and viral replication. Here, we report that type I interferon (IFN)-inducible miR-128 directly targets two sites in the TNPO3 mRNA, significantly downregulating TNPO3 mRNA and protein expression levels. Challenging miR-modulated Jurkat cells or primary CD4+ T-cells with wild-type (WT), replication-competent HIV-1 demonstrated that miR-128 reduces viral replication and delays spreading of infection. Manipulation of miR-128 levels in HIV-1 target cell lines and in primary CD4+ T-cells by overexpression or knockdown showed that reduction of TNPO3 levels by miR-128 significantly affects HIV-1 replication but not murine leukemia virus (MLV) infection and that miR-128 modulation of HIV-1 replication is reduced with TNPO3-independent HIV-1 virus, suggesting that miR-128-indued TNPO3 repression contributes to the inhibition of HIV-1 replication. Finally, we determine that anti-miR-128 partly neutralizes the IFN-mediated block of HIV-1. Thus, we have established a novel role of miR-128 in antiviral defense in human cells, namely inhibiting HIV-1 replication by altering the cellular milieu through targeting factors that include TNPO3. IMPORTANCE HIV-1 is the causative agent of AIDS. During HIV-1 infection, type I interferons (IFNs) are induced, and their effectors limit HIV-1 replication at multiple steps in its life cycle. However, the cellular targets of INFs are still largely unknown. In this study, we identified the interferon-inducible microRNA (miR) miR-128, a novel antiviral mediator that suppresses the expression of the host gene TNPO3, which is known to modulate HIV-1 replication. Notably, we observe that anti-miR-128 partly neutralizes the IFN-mediated block of HIV-1. Elucidation of the mechanisms through which miR-128 impairs HIV-1 replication may provide novel candidates for the development of therapeutic interventions.

scholarly journals Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4192-4204 ◽  
Author(s):  
Shokrollah Elahi ◽  
Toshiro Niki ◽  
Mitsuomi Hirashima ◽  
Helen Horton
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Viral Infections ◽  
Kinase Inhibitor ◽  
Type I ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induce Resistance ◽  
Domain 3 ◽  
Hiv 1

Abstract Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4+ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4+ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4+ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection.

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

Some mechanisms of FLIP expression in inhibition of HIV-1 replication in Jurkat cells, CD4+ T cells and PBMCs

2013 ◽  
Vol 228 (12) ◽  
pp. 2305-2313 ◽  
Author(s):  
Jiying Tan ◽  
Xue Wang ◽  
Krishnakumar Devadas ◽  
Jiangqin Zhao ◽  
Panhe Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Jurkat Cells ◽  
Hiv 1

scholarly journals Cytopathic Killing of Peripheral Blood CD4+ T Lymphocytes by Human Immunodeficiency Virus Type 1 Appears Necrotic rather than Apoptotic and Does Not Require env

2002 ◽  
Vol 76 (10) ◽  
pp. 5082-5093 ◽  
Author(s):  
Michael J. Lenardo ◽  
Sara B. Angleman ◽  
Viengngeun Bounkeua ◽  
Joseph Dimas ◽  
Melody G. Duvall ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Fluorescent Protein ◽  
Jurkat Cells ◽  
Coding Region ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT An important unresolved issue of AIDS pathogenesis is the mechanism of human immunodeficiency virus (HIV)-induced CD4+ T-lymphocyte destruction. We show here that HIV type 1 (HIV-1) exerts a profound cytopathic effect upon peripheral blood CD4+ T lymphocytes that resembles necrosis rather than apoptosis. Necrotic cytopathology was found with both laboratory-adapted strains and primary isolates of HIV-1. We carefully investigated the role of env, which has been previously implicated in HIV cytopathicity. HIV-1 stocks with equivalent infectivity were prepared from constructs with either an intact or mutated env coding region and pseudotyped with the glycoprotein of vesicular stomatitis virus (VSV-G) so that the HIV envelope was not rate-limiting for infection. Infected Jurkat T cells died whether or not env was intact; however, the expression of env accelerated death significantly. The accelerated death was blocked by protease inhibitors, indicating that it was due to reinfection by newly produced virus in env+ cultures. Accordingly, we found no disparity in kinetics in CD4lo Jurkat cells. In highly infected peripheral blood T cells, profound necrosis occurred equivalently with both env+ and env− stocks of HIV-1. We also found that HIV-1 cytopathicity was undiminished by the absence of nef. However, viral stocks made by complementation or packaging of HIV-1 genomes with the natural protein-coding sequences replaced by the green fluorescent protein were highly infectious but not cytopathic. Thus, env can accelerate cell death chiefly as an entry function, but one or more viral functions other than env or nef is essential for necrosis of CD4+ T cells induced by HIV-1.

scholarly journals HIV-1 infection induces a type I IFN response in primary CD4+ T cells

Retrovirology ◽  
2013 ◽  
Vol 10 (S1) ◽  
Author(s):  
Jolien Vermeire ◽  
Veronica Iannucci ◽  
Evelien Naessens ◽  
Kathleen Van Landeghem ◽  
Hanne Vanderstraeten ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Type I ◽  
Type I Ifn ◽  
Hiv 1

scholarly journals Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells

2005 ◽  
Vol 102 (39) ◽  
pp. 13974-13979 ◽  
Author(s):  
J.-P. Herbeuval ◽  
A. W. Hardy ◽  
A. Boasso ◽  
S. A. Anderson ◽  
M. J. Dolan ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Type I Ifn ◽  
Hiv 1

scholarly journals Expression of the c-myc Proto-oncogene Is Essential for HIV-1 Infection in Activated T Cells

1999 ◽  
Vol 189 (9) ◽  
pp. 1391-1398 ◽  
Author(s):  
Yu Sun ◽  
Edward A. Clark
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Nuclear Import ◽  
Antisense Oligonucleotide ◽  
Cd4 T Cells ◽  
Apoptotic Cell ◽  
Activated T Cells ◽  
Cell Cycle Entry ◽  
Phosphorothioate Oligodeoxynucleotides ◽  
Hiv 1

We previously found that activation of primary CD4+ T cells via both the T cell antigen receptor (TCR) and CD28 is required for HIV-1 DNA to be translocated from the cytoplasm to the nucleus. Here we report that expression of c-Myc protein in CD4+ T cells is induced only after such costimulation. In addition, cyclosporin A not only inhibits nuclear import of HIV-1 DNA but also inhibits expression of c-Myc protein. Because of these correlations, we tested whether c-Myc is necessary for nuclear import of HIV-1 DNA. Specific c-myc antisense, but not sense or non-sense, phosphorothioate oligodeoxynucleotides selectively induced the accumulation of two NH2-terminally truncated c-Myc proteins and abolished HIV-1 genome entry into host nuclei. Consequently, both virus replication and HIV-1–induced apoptotic cell death were inhibited. Synthesis of viral full-length DNA was not affected. Specific c-myc antisense oligonucleotide inhibited HIV-1 infection under conditions that did not affect cell cycle entry or proliferation. Thus, c-Myc appears to regulate HIV-1 DNA nuclear import via a mechanism distinct from those controlling entry into the cell cycle.

scholarly journals Factors Secreted by Human T Lymphotropic Virus Type I (HTLV-I)–infected Cells Can Enhance or Inhibit Replication of HIV-1 in HTLV-I–uninfected Cells: Implications for In Vivo Coinfection with HTLV-I and HIV-1

1998 ◽  
Vol 187 (10) ◽  
pp. 1689-1697 ◽  
Author(s):  
Hiroyuki Moriuchi ◽  
Masako Moriuchi ◽  
Anthony S. Fauci
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Rapid Progression ◽  
Type I ◽  
Hiv Disease ◽  
T Lymphotropic Virus ◽  
Cc Chemokines ◽  
Hiv 1

It remains controversial whether human T lymphotropic virus type I (HTLV-I) coinfection leads to more rapid progression of human immunodeficiency virus (HIV) disease in dually infected individuals. To investigate whether HTLV-I infection of certain cells can modulate HIV-1 infection of surrounding cells, primary CD4+ T cells were treated with cell-free supernatants from HTLV-I–infected MT-2 cell cultures. The primary CD4+ T cells became resistant to macrophage (M)-tropic HIV-1 but highly susceptible to T cell (T)-tropic HIV-1. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1α, and MIP-1β in the MT-2 cell supernatants were identified as the major suppressive factors for M-tropic HIV-1 as well as the enhancers of T-tropic HIV-1 infection, whereas soluble Tax protein increased susceptibility to both M- and T-tropic HIV-1. The effect of Tax or CC chemokines on T-tropic HIV-1 was mediated, at least in part, by increasing HIV Env-mediated fusogenicity. Our data suggest that the net effect of HTLV-I coinfection in HIV-infected individuals favors the transition from M- to T-tropic HIV phenotype, which is generally indicative of progressive HIV disease.

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