scholarly journals The Landscape of IFN/ISG Signaling in HIV-1-Infected Macrophages and Its Possible Role in the HIV-1 Latency

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2378
Author(s):  
Masyelly Rojas ◽  
Patricia Luz-Crawford ◽  
Ricardo Soto-Rifo ◽  
Sebastián Reyes-Cerpa ◽  
Daniela Toro-Ascuy
Keyword(s):  
Innate Immune ◽  
Viral Fitness ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Reservoirs ◽  
Immunodeficiency Virus ◽  
Latent Hiv ◽  
Hiv 1

A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation. Macrophages play a protagonist role in this context since they are persistently infected while being a major effector of the innate immune response through the generation of type-I interferons (type I IFN) and IFN-stimulated genes (ISGs). The balance in the IFN signaling and the ISG induction is critical to promote a successful HIV-1 infection. Classically, the IFNs response is fine-tuned by opposing promotive and suppressive signals. In this context, it was described that HIV-1-infected macrophages can also synthesize some antiviral effector ISGs and, positive and negative regulators of the IFN/ISG signaling. Recently, epitranscriptomic regulatory mechanisms were described, being the N6-methylation (m6A) modification on mRNAs one of the most relevant. The epitranscriptomic regulation can affect not only IFN/ISG signaling, but also type I IFN expression, and viral fitness through modifications to HIV-1 RNA. Thus, the establishment of replication-competent latent HIV-1 infected macrophages may be due to non-classical mechanisms of type I IFN that modulate the activation of the IFN/ISG signaling network.

scholarly journals Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro

2008 ◽  
Vol 82 (8) ◽  
pp. 3997-4006 ◽  
Author(s):  
John C. Tilton ◽  
Maura M. Manion ◽  
Marlise R. Luskin ◽  
Alison J. Johnson ◽  
Andy A. Patamawenu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
De Novo ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Production ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a flow cytometric assay to detect IFN-α-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-α production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-α production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-α production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-α2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-α production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.

scholarly journals Kinetics of Early Innate Immune Activation during HIV-1 Infection of Humanized Mice

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Jessica Katy Skelton ◽  
Ana Maria Ortega-Prieto ◽  
Steve Kaye ◽  
Jose Manuel Jimenez-Guardeño ◽  
Jane Turner ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Activation ◽  
Innate Immune ◽  
Model Systems ◽  
Humanized Mice ◽  
Type I ◽  
Innate Immune Activation ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.

scholarly journals Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 320 ◽  
Author(s):  
Alexandra P. M. Cloherty ◽  
Anusca G. Rader ◽  
Brandon Compeer ◽  
Carla M. S. Ribeiro
Keyword(s):  
Therapeutic Potential ◽  
Innate Immune ◽  
Health Concern ◽  
Restriction Factor ◽  
Viral Reservoirs ◽  
Minimal Restriction ◽  
Immunodeficiency Virus ◽  
A Cell ◽  
Species Specific ◽  
Hiv 1

Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. It is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for HIV-1. It has been long accepted that the restriction factor tripartite motif protein 5 isoform alpha (TRIM5α) restricts HIV-1 infection in a species-specific manner, with rhesus macaque TRIM5α strongly restricting HIV-1, and human TRIM5α having a minimal restriction capacity. However, several recent studies underscore human TRIM5α as a cell-dependent HIV-1 restriction factor. Here, we present an overview of the latest research on human TRIM5α and propose a novel conceptualization of TRIM5α as a restriction factor with a varied portfolio of antiviral functions, including mediating HIV-1 degradation through autophagy- and proteasome-mediated mechanisms, and acting as a viral sensor and effector of antiviral signaling. We have also expanded on the protective antiviral roles of autophagy and outline the therapeutic potential of autophagy modulation to intervene in chronic HIV-1 infection.

scholarly journals CD4 Binding Affinity Determines Human Immunodeficiency Virus Type 1-Induced Alpha Interferon Production in Plasmacytoid Dendritic Cells

2008 ◽  
Vol 82 (17) ◽  
pp. 8900-8905 ◽  
Author(s):  
Sabrina Haupt ◽  
Norbert Donhauser ◽  
Chawaree Chaipan ◽  
Philipp Schuster ◽  
Bridget Puffer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Binding Affinity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Plasmacytoid dendritic cells (PDC) are major producers of type I interferons (IFN) in response to human immunodeficiency virus type 1 (HIV-1) infection. To better define the underlying mechanisms, we studied the magnitude of alpha IFN (IFN-α) induction by recombinant viruses containing changes in the Env protein that impair or disrupt CD4 binding or expressing primary env alleles with differential coreceptor tropism. We found that the CD4 binding affinity but not the viral coreceptor usage is critical for the attachment of autofluorescing HIV-1 to PDC and for subsequent IFN-α induction. Our results illustrate the importance of the gp120-CD4 interaction in determining HIV-1-induced immune stimulation via IFN-α production.

scholarly journals Insertions in the Reverse Transcriptase Increase both Drug Resistance and Viral Fitness in a Human Immunodeficiency Virus Type 1 Isolate Harboring the Multi-Nucleoside Reverse Transcriptase Inhibitor Resistance 69 Insertion Complex Mutation

2002 ◽  
Vol 76 (20) ◽  
pp. 10546-10552 ◽  
Author(s):  
Miguel E. Quiñones-Mateu ◽  
Mahlet Tadele ◽  
Mariona Parera ◽  
Antonio Mas ◽  
Jan Weber ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Viral Fitness ◽  
Wild Type ◽  
Sequence Context ◽  
Recombinant Viruses ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Recent studies have shown that the accumulation of multiple mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance may be grouped as multi-NRTI resistance (MNR) complexes. In this study, we have examined the viral fitness of recombinant viruses carrying the reverse transcriptase (RT) of a human immunodeficiency virus type 1 (HIV-1) primary isolate harboring mutations comprising the MNR 69 insertion complex. Different RT mutants were prepared in the sequence context of either the wild-type RT sequence of the HIV-1BH10 isolate or the sequence found in a clinical HIV-1 isolate with the MNR 69 insertion mutation. As expected, in the presence of zidovudine, recombinant viruses harboring the MNR RT from the patient were more fit than wild-type viruses. However, in the absence of drug, the virus with the RT from the original clinical isolate (SS) was more fit than (i) the wild-type virus with an engineered serine insertion between residues 69 and 70 (T69SSS) and (ii) the recombinant virus with the MNR RT where the insertion was removed (2S0S). These results suggest that RT insertions, in the right sequence context (i.e., additional mutations contained in the MNR 69 insertion complex), enhance NRTI resistance and may improve viral fitness. Thus, comparing complex mutation patterns with viral fitness may help to elucidate the role of uncharacterized drug resistance mutations in antiretroviral treatment failure.

scholarly journals Sustained Induction of NF-κB Is Required for Efficient Expression of Latent Human Immunodeficiency Virus Type 1

2007 ◽  
Vol 81 (11) ◽  
pp. 6043-6056 ◽  
Author(s):  
Samuel A. Williams ◽  
Hakju Kwon ◽  
Lin-Feng Chen ◽  
Warner C. Greene
Keyword(s):  
Human Immunodeficiency Virus ◽  
Okadaic Acid ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Tnf Α ◽  
Immunodeficiency Virus ◽  
Latent Hiv ◽  
Hiv 1 ◽  
Stimulation Of

ABSTRACT Cells harboring infectious, but transcriptionally latent, human immunodeficiency virus type 1 (HIV-1) proviruses currently pose an insurmountable barrier to viral eradication in infected patients. To better understand the molecular basis for HIV-1 latency, we used the J-Lat model of postintegration HIV-1 latency to assess the kinetic relationship between the induction of NF-κB and the activation of latent HIV-1 gene expression. Chromatin immunoprecipitation analyses revealed an oscillating pattern of RelA recruitment to the HIV-1 long terminal repeat (LTR) during continuous tumor necrosis factor alpha (TNF-α) stimulation. RNA polymerase II (Pol II) recruitment to the HIV-1 LTR closely mirrored RelA binding. Transient stimulation of cells with TNF-α for 15 min induced only a single round of RelA and RNA Pol II binding and failed to induce robust expression of latent HIV-1. Efficient formation of elongated HIV-1 transcripts required sustained induction by NF-κB, which promoted de novo synthesis of Tat. Cyclin-dependent kinase 9 (CDK9) and serine-2-phosphorylated RNA Pol II were rapidly recruited to the HIV-1 LTR after NF-κB induction; however, these elongating polymerase complexes were progressively dephosphorylated in the absence of Tat. Okadaic acid promoted sustained serine-2 phosphorylation of the C-terminal domain of RNA Pol II and stimulated efficient transcriptional elongation and HIV-1 expression in the absence of Tat. These findings underscore important differences between NF-κB and Tat stimulation of RNA Pol II elongation. While NF-κB binding to the HIV-1 LTR induces serial waves of efficient RNA Pol II initiation, elongation is impaired by the action of an okadaic acid-sensitive phosphatase that dephosphorylates the C-terminal domain of RNA Pol II. Conversely, the action of this phosphatase is overcome in the presence of Tat, promoting very efficient RNA Pol II elongation.

scholarly journals Changes in Human Immunodeficiency Virus Type 1 Gag at Positions L449 and P453 Are Linked to I50V Protease Mutants In Vivo and Cause Reduction of Sensitivity to Amprenavir and Improved Viral Fitness In Vitro

2002 ◽  
Vol 76 (15) ◽  
pp. 7398-7406 ◽  
Author(s):  
Michael F. Maguire ◽  
Rosario Guinea ◽  
Philip Griffin ◽  
Sarah Macmanus ◽  
Robert C. Elston ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Fitness ◽  
Wild Type Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Gag protease cleavage sites (CS) undergo sequence changes during the development of resistance to several protease inhibitors (PIs). We have analyzed the association of sequence variation at the p7/p1 and p1/p6 CS in conjunction with amprenavir (APV)-specific protease mutations following PI combination therapy with APV. Querying a central resistance data repository resulted in the detection of significant associations (P < 0.001) between the presence of APV protease signature mutations and Gag L449F (p1/p6 LP1′F) and P453L (p1/p6 PP5′L) CS changes. In population-based sequence analyses the I50V mutant was invariably linked to either L449F or P453L. Clonal analysis revealed that both CS mutations were never present in the same genome. Sequential plasma samples from one patient revealed a transition from I50V M46L P453L viruses at early time points to I50V M46I L449F viruses in later samples. Various combinations of the protease and Gag mutations were introduced into the HXB2 laboratory strain of HIV-1. In both single- and multiple-cycle assay systems and in the context of I50V, the L449F and P453L changes consistently increased the 50% inhibitory concentration of APV, while the CS changes alone had no measurable effect on inhibitor sensitivity. The decreased in vitro fitness of the I50V mutant was only partially improved by addition of either CS change (I50V M46I L449F mutant replicative capacity ≈ 16% of that of wild-type virus). Western blot analysis of Pr55 Gag precursor cleavage products from infected-cell cultures indicated accumulation of uncleaved Gag p1-p6 in all I50V viruses without coexisting CS changes. Purified I50V protease catalyzed cleavage of decapeptides incorporating the L449F or P453L change 10-fold and 22-fold more efficiently than cleavage of the wild-type substrate, respectively. HIV-1 protease CS changes are selected during PI therapy and can have effects on both viral fitness and phenotypic resistance to PIs.

scholarly journals Oncogenic Human T-Cell Lymphotropic Virus Type 1 Tax Suppression of Primary Innate Immune Signaling Pathways

2015 ◽  
Vol 89 (9) ◽  
pp. 4880-4893 ◽  
Author(s):  
Jinhee Hyun ◽  
Juan Carlos Ramos ◽  
Ngoc Toomey ◽  
Siddharth Balachandran ◽  
Alfonso Lavorgna ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Host Defense ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACTHuman T-cell lymphotropic virus type I (HTLV-1) is an oncogenic retrovirus considered to be the etiological agent of adult T-cell leukemia (ATL). The viral transactivator Tax is regarded as the oncoprotein responsible for contributing toward the transformation process. Here, we demonstrate that Tax potently inhibits the activity of DEx(D/H) box helicases RIG-I and MDA5 as well as Toll-dependent TIR-domain-containing adapter-inducing interferon-β (TRIF), which function as cellular sensors or mediators of viral RNA and facilitate innate immune responses, including the production of type I IFN. Tax manifested this function by binding to the RIP homotypic interaction motif (RHIM) domains of TRIF and RIP1 to disrupt interferon regulatory factor 7 (IRF7) activity, a critical type I IFN transcription factor. These data provide further mechanistic insight into HTLV-1-mediated subversion of cellular host defense responses, which may help explain HTLV-1-related pathogenesis and oncogenesis.IMPORTANCEIt is predicted that up to 15% of all human cancers may involve virus infection. For example, human T-cell lymphotropic virus type 1 (HTLV-1) has been reported to infect up to 25 million people worldwide and is the causative agent of adult T-cell leukemia (ATL). We show here that HTLV-1 may be able to successfully infect the T cells and remain latent due to the virally encoded product Tax inhibiting a key host defense pathway. Understanding the mechanisms by which Tax subverts the immune system may lead to the development of a therapeutic treatment for HTLV-1-mediated disease.

scholarly journals Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Jintao Zhang ◽  
Chunyuan Zhao ◽  
Wei Zhao
Keyword(s):  
Innate Immunity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Responses ◽  
Public Health Challenges ◽  
Host Innate Immunity ◽  
Efficient Elimination

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.

scholarly journals Cell-to-cell infection by HIV contributes over half of virus infection

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Shingo Iwami ◽  
Junko S Takeuchi ◽  
Shinji Nakaoka ◽  
Fabrizio Mammano ◽  
François Clavel ◽  
...  
Keyword(s):  
Virus Infection ◽  
Viral Infection ◽  
Quantitative Information ◽  
Viral Fitness ◽  
Cell Infection ◽  
Immunodeficiency Virus ◽  
Mathematical Investigation ◽  
Infection Mode ◽  
Hiv 1

Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread.

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