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 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 Concurrent administration of IFNα14 and cART in TKO-BLT mice enhances suppression of HIV-1 viremia but does not eliminate the latent reservoir

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kathrin Sutter ◽  
Kerry J. Lavender ◽  
Ronald J. Messer ◽  
Marek Widera ◽  
Katie Williams ◽  
...  
Keyword(s):  
Infection Type ◽  
Treatment Interruption ◽  
Type I Interferons ◽  
Latent Reservoir ◽  
Type I ◽  
Concurrent Administration ◽  
Viral Dna ◽  
Therapy Interruption ◽  
Hiv 1

AbstractCombination antiretroviral therapy (cART) prevents HIV-1 replication but does not eliminate the latent reservoir and cure the infection. Type I interferons (IFN) mediate antiviral effects through different mechanisms than cART. We previously showed that IFNα14 is the most potent IFNα subtype against HIV-1 and that it can significantly reduce the HIV-1 proviral reservoir. This study sought to determine whether combining cART with IFNα14 therapy would produce greater reductions in HIV-1 viral and proviral loads than ART alone. Immunodeficient Rag2−/−γc−/−CD47−/− C57BL/6 mice were humanized by the BLT method, infected with HIV-1JR-CSF and the in vivo efficacy of cART was compared with combined cART/IFNα14 therapy. Infection was allowed to establish for 6 weeks prior to 4 weeks of treatment with oral cART either with or without IFNα14. Plasma viral RNA and splenic CD4+ T cell viral DNA levels were measured immediately after treatment and after 2 weeks of therapy interruption. Augmentation of cART with IFNα14 resulted in significantly enhanced suppression of HIV-1 plasma viremia. However, no significant reduction in total viral DNA was detectable. Furthermore, virus rebounded after treatment interruption to similar levels in both groups. Thus, augmentation of cART with IFNα14 resulted in a more pronounced reduction of HIV viremia levels over cART alone, but the effect was not potent enough to be detected at the viral DNA level or to prevent virus rebound following therapy interruption in immune system-humanized mice.

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 Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

JCI Insight ◽  
2017 ◽  
Vol 2 (12) ◽  
Author(s):  
Liang Cheng ◽  
Haisheng Yu ◽  
Guangming Li ◽  
Feng Li ◽  
Jianping Ma ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Type I Interferons ◽  
Cell Depletion ◽  
Type I ◽  
T Cell Depletion ◽  
Hiv 1

scholarly journals Complex Interplay between HIV-1 Capsid and MX2-Independent Alpha Interferon-Induced Antiviral Factors

2016 ◽  
Vol 90 (16) ◽  
pp. 7469-7480 ◽  
Author(s):  
Lorenzo Bulli ◽  
Luis Apolonia ◽  
Juliane Kutzner ◽  
Darja Pollpeter ◽  
Caroline Goujon ◽  
...  
Keyword(s):  
Host Cell ◽  
Reverse Transcription ◽  
Nuclear Import ◽  
Type I Interferons ◽  
Wild Type Virus ◽  
Type I ◽  
Wild Type ◽  
Complex Interplay ◽  
Hiv 1 ◽  
Effector Mechanisms

ABSTRACTType I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4+T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection.IMPORTANCEHIV-1 is the causative agent of AIDS. During acute HIV-1 infection, numerous proinflammatory cytokines are produced, including type I interferons (IFNs). IFNs can limit HIV-1 replication by inducing the expression of a set of antiviral genes that inhibit HIV-1 at multiple steps in its life cycle, including the postentry steps of reverse transcription and nuclear import. This is observed in cultured cell systems, as well as in clinical trials in HIV-1-infected patients. The identities of the cellular antiviral factors, their viral targets, and the underpinning mechanisms are largely unknown. We show here that the HIV-1 Capsid protein plays a central role in protecting the virus from IFN-induced inhibitors that block early postentry steps of infection. We further show that host cell cyclophilins play an important role in regulating these processes, thus highlighting the complex interplay between antiviral effector mechanisms and viral survival.

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 Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Norzawani Buang ◽  
Lunnathaya Tapeng ◽  
Victor Gray ◽  
Alessandro Sardini ◽  
Chad Whilding ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Lupus Erythematosus ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Systemic Lupus ◽  
Mitochondrial Abnormalities

AbstractThe majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.

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