scholarly journals HIV-1 trans-Infection Mediated by DCs: The Tip of the Iceberg of Cell-to-Cell Viral Transmission

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 39
Author(s):  
Daniel Perez-Zsolt ◽  
Dàlia Raïch-Regué ◽  
Jordana Muñoz-Basagoiti ◽  
Carmen Aguilar-Gurrieri ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Immune Responses ◽  
Ebola Virus ◽  
Viral Transmission ◽  
Productive Infection ◽  
Lectin Receptors ◽  
Enveloped Viruses ◽  
Cellular Targets ◽  
Trans Infection ◽  
Antigen Presenting ◽  
Hiv 1

HIV-1 cell-to-cell transmission is key for an effective viral replication that evades immunity. This highly infectious mechanism is orchestrated by different cellular targets that utilize a wide variety of processes to efficiently transfer HIV-1 particles. Dendritic cells (DCs) are the most potent antigen presenting cells that initiate antiviral immune responses, but are also the cells with highest capacity to transfer HIV-1. This mechanism, known as trans-infection, relies on the capacity of DCs to capture HIV-1 particles via lectin receptors such as the sialic acid-binding I-type lectin Siglec-1/CD169. The discovery of the molecular interaction of Siglec-1 with sialylated lipids exposed on HIV-1 membranes has enlightened how this receptor can bind to several enveloped viruses. The outcome of these interactions can either mount effective immune responses, boost the productive infection of DCs and favour innate sensing, or fuel viral transmission via trans-infection. Here we review these scenarios focusing on HIV-1 and other enveloped viruses such as Ebola virus or SARS-CoV-2.

scholarly journals Potential of recombinant Mycobacterium paragordonae expressing HIV-1 Gag as a prime vaccine for HIV-1 infection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Byoung-Jun Kim ◽  
Bo-Ram Kim ◽  
Yoon-Hoh Kook ◽  
Bum-Joon Kim
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Antibody Production ◽  
Vaccine Development ◽  
Cytotoxic T Lymphocyte ◽  
Mycobacterial Infection ◽  
Temperature Sensitive ◽  
T Lymphocyte Proliferation ◽  
Antigen Presenting ◽  
Hiv 1

Abstract Recombinant Mycobacterium strains such as recombinant BCG (rBCG) have received considerable attention for the HIV-1 vaccine development. Recently, we described a temperature-sensitive Mycobacterium paragordonae (Mpg) strain as a novel live tuberculosis vaccine that is safer and showed an enhanced protective effect against mycobacterial infection compared to BCG. We studied the possibility of developing a vaccine against HIV-1 infection using rMpg strain expressing the p24 antigen (rMpg-p24). We observed that rMpg-p24 can induce an increased p24 expression in infected antigen presenting cells (APCs) compared to rBCG-p24. We also observed that rMpg-p24 can induce enhanced p24 specific immune responses in vaccinated mice as evidenced by increased p24-specific T lymphocyte proliferation, gamma interferon induction, antibody production and cytotoxic T lymphocyte (CTL) responses. Furthermore, an rMpg-p24 prime and plasmid DNA boost showed an increased CTL response and antibody production compared to rBCG or rMpg alone. In summary, our study indicates that a live rMpg-p24 strain induced enhanced immune responses against HIV-1 Gag in vaccinated mice. Thus, rMpg-p24 may have potential as a preventive prime vaccine in a heterologous prime-boost regimen for HIV-1 infection.

scholarly journals Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models

2013 ◽  
Vol 58 (1) ◽  
pp. 120-127 ◽  
Author(s):  
Christopher Barton ◽  
J. Calvin Kouokam ◽  
Amanda B. Lasnik ◽  
Oded Foreman ◽  
Alexander Cambon ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Viral Infections ◽  
Antiviral Treatment ◽  
Enveloped Viruses ◽  
Minimal Toxicity ◽  
Human T Cell ◽  
Long Term Treatment ◽  
Hiv 1

ABSTRACTGriffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.

scholarly journals The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1299-1307 ◽  
Author(s):  
Alexandra A. Lambert ◽  
Caroline Gilbert ◽  
Manon Richard ◽  
André D. Beaulieu ◽  
Michel J. Tremblay
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Productive Infection ◽  
Virus Binding ◽  
Virus Propagation ◽  
Cell Surface Molecule ◽  
Lectin Receptor ◽  
Trans Infection ◽  
Hiv 1

Abstract The dynamic interplay between dendritic cells (DCs) and human immunodeficiency virus type-1 (HIV-1) is thought to result in viral dissemination and evasion of antiviral immunity. Although initial observations suggested that the C-type lectin receptor (CLR) DC-SIGN was responsible for the trans-infection function of the virus, subsequent studies demonstrated that trans-infection of CD4+ T cells with HIV-1 can also occur through DC-SIGN–independent mechanisms. We demonstrate that a cell surface molecule designated DCIR (for DCimmunoreceptor), a member of a recently described family of DC-expressing CLRs, can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4+ T cells from human immature monocyte-derived DCs. The contribution of DCIR to these processes was revealed using DCIR-specific siRNAs and a polyclonal antibody specific for the carbohydrate recognition domain of DCIR. Data from transfection experiments indicated that DCIR acts as a ligand for HIV-1 and is involved in events leading to productive virus infection. Finally, we show that the neck domain of DCIR is important for the DCIR-mediated effect on virus binding and infection. These results point to a possible role for DCIR in HIV-1 pathogenesis by supporting the productive infection of DCs and promoting virus propagation.

scholarly journals Novel Methodology for the Detection of Enveloped Viruses

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 52
Author(s):  
Patricia Resa-Infante ◽  
Itziar Erkizia ◽  
Jon Ander Nieto-Garai ◽  
Maier Lorizate ◽  
Nuria Izquierdo-Useros ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Direct Method ◽  
Human Mobility ◽  
Specific Interaction ◽  
Negative Control ◽  
Target Cells ◽  
Set Domain ◽  
Enveloped Viruses ◽  
Viral Particles ◽  
Hiv 1

Viral infections in humans cause a huge burden in worldwide healthcare that has increased due to the emergence of new pathogenic viruses, such as in the recent Ebola virus (EBOV) outbreaks. Viral particles in body fluids are often at very low levels, making diagnosis difficult. In order to address this problem, we have developed a new detection platform to isolate and detect different enveloped viruses. We have recently identified that sialic acid-binding Ig‑like lectin 1 (Siglec-1/CD169) is one cellular receptor used by EBOV and HIV-1 to enter myeloid cells, key target cells for infection and pathogenesis. For viral uptake, the V-set domain of this myeloid cell receptor recognizes the gangliosides of viral membranes that were dragged during viral budding from the plasma membrane of infected cells. We took advantage of this specific interaction between Siglec‑1 and viral gangliosides to develop a new detection methodology. We have generated a recombinant protein that contains the V-set domain of Siglec-1 fused to the human IgG Fc domain for anchoring in latex beads. These coated beads allow the isolation of viral particles and their measurement by flow cytometry. We have tested its efficacy to detect HIV-1 and EBOV and its specificity by using anti-Siglec‑1 antibodies that prevent the interaction and serve as a negative control. To test the capacity of our method, we used synthetic liposomes to assess the effect of ganglioside concentration in membranes as well as the size of viral particles. This methodology would facilitate the diagnosis of infections by concentrating viral particles in a fast and direct method. At a time when global human mobility facilitates the dissemination of infectious agents, our approach represents a rapid and effective method to maximize the identification of both known and emerging enveloped viruses as part of public health viral surveillance strategies.

scholarly journals Interleukin-12p70 Expression by Dendritic Cells of HIV-1-Infected Patients Fails to Stimulategag-Specific Immune Responses

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ellen Van Gulck ◽  
Nathalie Cools ◽  
Derek Atkinson ◽  
Lotte Bracke ◽  
Katleen Vereecken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Hiv Replication ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Hiv 1 ◽  
Unique Capability

A variety of immune-based therapies has been developed in order to boost or induce protective CD8+T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2gagmRNA enhances their capacity to induce HIVgag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2gag-expressing DCs to expand functional HIV-specific CD8+T cells. However, although most of the patients had detectablegag-specific CD8+T cell responses, no significant differences in the level of expansion of functional CD8+T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

scholarly journals Capsaicin activates TRPV1 in human Langerhans cells and inhibits mucosal HIV-1 transmission via secreted CGRP

2021 ◽  
Author(s):  
Emmanuel Cohen ◽  
Aiwei Zhu ◽  
Cédric Auffray ◽  
Morgane Bomsel ◽  
Yonatan Ganor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ion Channel ◽  
Cd4 T Cells ◽  
Langerhans Cells ◽  
Dependent Manner ◽  
Mucosal Transmission ◽  
Trans Infection ◽  
Antigen Presenting ◽  
Hiv 1

AbstractUpon its mucosal transmission, human immunodeficiency virus type 1 (HIV-1) rapidly targets resident antigen-presenting Langerhans cells (LCs) in genital epithelia, which subsequently trans-infect CD4+ T-cells. We previously described an inhibitory neuro-immune sensory mucosal crosstalk, whereby peripheral pain-sensing nociceptor neurons, innervating all mucosal epithelia and associating with LCs, secret the neuropeptide calcitonin gene-related peptide (CGRP) that strongly inhibits HIV-1 trans-infection. Moreover, we reported that LCs secret low levels of CGRP that are further increased by CGRP itself via an autocrine/paracrine mechanism. As nociceptors secret CGRP following activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), we investigated whether LCs also express functional TRPV1. We found that human LCs expressed TRPV1 mRNA and protein. TRPV1 in LCs was functional, as the TRPV1 agonists capsaicin (CP) and resiniferatoxin (RTX) induced Ca2+ influx in a dose-dependent manner. Treatment of LCs with CP and the TRPV1 agonist rutaecarpine (Rut) increased CGRP secretion, reaching concentrations close to its IC50 for inhibition of HIV-1 trans-infection. Accordingly, CP significantly inhibited HIV-1 trans-infection, which was abrogated by antagonists of both TRPV1 and the CGRP receptor. Finally, pre-treatment of inner foreskin tissue explants with CP markedly increased CGRP secretion, and upon subsequent polarized exposure to HIV-1, inhibited increase in LC-T-cell conjugate formation and T-cell infection. Together, our results reveal that alike nociceptors, LCs express functional TRPV1, whose activation induces CGRP secretion that inhibits mucosal HIV-1 transmission. Our studies could permit re-positioning of formulations containing TRPV1 agonists, already approved for pain relief, as novel topical microbicides against HIV-1.Significance StatementUpon its sexual transmission, HIV-1 targets different types of mucosal immune cells, such as antigen-presenting Langerhans cells (LCs). In turn, LCs transfer HIV-1 to its principal cellular targets, namely CD4+ T-cells, in a process termed trans-infection. We previously discovered that the mucosal neuropeptide CGRP strongly inhibits trans-infection. CGRP is principally secreted from pain-sensing peripheral neurons termed nociceptors, once activated via their TRPV1 ion channel. Herein, we reveal that LCs also express functional TRPV1, whose activation induces secretion of CGRP that inhibits mucosal HIV-1 transmission. Accordingly, molecules activating TRPV1 and inducing CGRP secretion could be used to prevent mucosal HIV-1 transmission. This approach represents an original neuro-immune strategy to fight HIV-1.

scholarly journals HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Anna Lisa Remoli ◽  
Giulia Marsili ◽  
Edvige Perrotti ◽  
Chiara Acchioni ◽  
Marco Sgarbanti ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
Cellular Protein ◽  
Cellular Targets ◽  
Host Immune Responses ◽  
Cellular Transcription Factor ◽  
Regulatory Circuit ◽  
Mechanistic Basis ◽  
Cellular Transcription ◽  
Hiv 1

ABSTRACTIn addition to its ability to regulate HIV-1 promoter activation, the viral transactivator Tat also functions as a determinant of pathogenesis and disease progression by directly and indirectly modulating the host anti-HIV response, largely through the capacity of Tat to interact with and modulate the activities of multiple host proteins. We previously demonstrated that Tat modulated both viral and host transcriptional machinery by interacting with the cellular transcription factor interferon regulatory factor 1 (IRF-1). In the present study, we investigated the mechanistic basis and functional significance of Tat−IRF-1 interaction and demonstrate that Tat dramatically decreased IRF-1 protein stability. To accomplish this, Tat exploited the cellular HDM2 (human double minute 2 protein) ubiquitin ligase to accelerate IRF-1 proteasome-mediated degradation, resulting in a quenching of IRF-1 transcriptional activity during HIV-1 infection. These data identify IRF-1 as a new target of Tat-induced modulation of the cellular protein machinery and reveal a new strategy developed by HIV-1 to evade host immune responses.IMPORTANCECurrent therapies have dramatically reduced morbidity and mortality associated with HIV infection and have converted infection from a fatal pathology to a chronic disease that is manageable via antiretroviral therapy. Nevertheless, HIV-1 infection remains a challenge, and the identification of useful cellular targets for therapeutic intervention remains a major goal. The cellular transcription factor IRF-1 impacts various physiological functions, including the immune response to viral infection. In this study, we have identified a unique mechanism by which HIV-1 evades IRF-1-mediated host immune responses and show that the viral protein Tat accelerates IRF-1 proteasome-mediated degradation and inactivates IRF-1 function. Restoration of IRF-1 functionality may thus be regarded as a potential strategy to reinstate both a direct antiviral response and a more broadly acting immune regulatory circuit.

scholarly journals SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

2015 ◽  
Vol 89 (14) ◽  
pp. 6994-7006 ◽  
Author(s):  
Diana Ayinde ◽  
Timothée Bruel ◽  
Sylvain Cardinaud ◽  
Françoise Porrot ◽  
Julia G. Prado ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Cytotoxic T Lymphocytes ◽  
Viral Proteins ◽  
Productive Infection ◽  
Restriction Factors ◽  
Adaptive Immune Responses ◽  
Mhc I ◽  
Adaptive Immune ◽  
Hiv 1

ABSTRACTMonocyte-derived dendritic cells (MDDC) stimulate CD8+cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses.IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

scholarly journals DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

2020 ◽  
Author(s):  
Michel Thépaut ◽  
Joanna Luczkowiak ◽  
Corinne Vivès ◽  
Nuria Labiod ◽  
Isabelle Bally ◽  
...  
Keyword(s):  
Innate Immune ◽  
Cell Infection ◽  
Lectin Receptors ◽  
Sign Recognition ◽  
Virus Transfer ◽  
Molecular Events ◽  
Trans Infection ◽  
Direct Cell ◽  
Multiple Interaction ◽  
Antigen Presenting

SummaryThe efficient spread of SARS-CoV-2 resulted in a pandemic that is unique in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLRS) of antigen-presenting cells, widely present in air mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2+ cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. Thus, we described a mechanism potentiating viral capture and spreading of infection. Early involvement of APCs opens new avenues for understanding and treating the imbalanced innate immune response observed in COVID-19 pathogenesis

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