TLR7 Activation of Macrophages by Imiquimod Inhibits HIV Infection through Modulation of Viral Entry Cellular Factors

The Toll-like receptor (TLR) 7 is a viral sensor for detecting single-stranded ribonucleic acid (ssRNA), the activation of which can induce intracellular innate immunity against viral infections. Imiquimod, a synthetic ligand for TLR7, has been successfully used for the topical treatment of genital/perianal warts in immunocompetent individuals. We studied the effect of imiquimod on the human immunodeficiency virus (HIV) infection of primary human macrophages and demonstrated that the treatment of cells with imiquimod effectively inhibited infection with multiple strains (Bal, YU2, and Jago) of HIV. This anti-HIV activity of imiquimod was the most potent when macrophages were treated prior to infection. Infection of macrophages with pseudotyped HIV NL4-3-∆Env-eGFP-Bal showed that imiquimod could block the viral entry. Further mechanistic studies revealed that while imiquimod had little effect on the interferons (IFNs) expression, its treatment of macrophages resulted in the increased production of the CC chemokines (human macrophage inflammatory protein-1 alpha (MIP-1α), MIP-1β, and upon activation regulated normal T cells expressed and secreted (RANTES)), the natural ligands of HIV entry co-receptor CCR5, and decreased the expression of CD4 and CCR5. The addition of the antibodies against the CC chemokines to macrophage cultures could block imiquimod-mediated HIV inhibition. These findings provide experimental evidence to support the notion that TLR7 participates in the intracellular immunity against HIV in macrophages, suggesting the further clinical evaluation of imiquimod for its additional benefit of treating genital/perianal warts in people infected with HIV.

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Human Immunodeficiency Virus (HIV)-Resistant CD4+ UT-7 Megakaryocytic Human Cell Line Becomes Highly HIV-1 and HIV-2 Susceptible Upon CXCR4 Transfection: Induction of Cell Differentiation by HIV-1 Infection

Blood ◽

10.1182/blood.v89.8.2670 ◽

1997 ◽

Vol 89 (8) ◽

pp. 2670-2678 ◽

Cited By ~ 17

Author(s):

Marta Baiocchi ◽

Eleonora Olivetta ◽

Cristiana Chelucci ◽

Anna Claudia Santarcangelo ◽

Roberta Bona ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Cell Line ◽

Viral Entry ◽

Human Cell Line ◽

Immunodeficiency Virus ◽

Hiv Entry ◽

Stromal Cell Derived Factor ◽

Hiv 1

Abstract Recent findings have shown that the expression of the seven trans-membrane G-protein–coupled CXCR4 (the receptor for the stromal cell-derived factor [SDF]-1 chemokine) is necessary for the entry of T-lymphotropic human immunodeficiency virus (HIV) strains, acting as a coreceptor of the CD4 molecule. In the human system, the role of CXCR4 in HIV infection has been determined through env-mediated cell fusion assays and confirmed by blocking viral entry in CD4+/CXCR4+ cells by SDF-1 pretreatment. We observed that the human megakaryoblastic CD4+ UT-7 cell line fails to express CXCR4 RNA and is fully resistant to HIV entry. Transfection of an expression vector containing the CXCR4 c-DNA rendered UT-7 cells readily infectable by different T-lymphotropic syncytium-inducing HIV-1 and HIV-2 isolates. Interestingly, HIV-1 infection of CXCR4 expressing UT-7 cells (named UT-7/fus) induces the formation of polynucleated cells through a process highly reminiscent of megakaryocytic differentiation and maturation. On the contrary, no morphologic changes were observed in HIV-2–infected UT-7/fus cells. These findings further strengthen the role of CXCR4 as a molecule necessary for the replication of T-lymphotropic HIV-1 and HIV-2 isolates and provide a useful model to study the functional role of CD4 coreceptors in HIV infection.

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Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers

Journal of Virology ◽

10.1128/jvi.00118-15 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5502-5514 ◽

Cited By ~ 24

Author(s):

Wendy E. Walker ◽

Sebastian Kurscheid ◽

Samit Joshi ◽

Charlie A. Lopez ◽

Gerald Goh ◽

...

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Viral Entry ◽

Natural Resistance ◽

Elite Controllers ◽

Hiv Replication ◽

Inflammatory Protein ◽

Genes Encoding ◽

Hiv Seropositive

ABSTRACTElite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4+T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4+T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1α (MIP-1α),CCL3andCCL3L1, were found to be upregulated. The MIP-1α, MIP-1β, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1α and/or MIP-1β at the protein level. The supernatant from resistant EC cells contained MIP-1α and MIP-1β and was sufficient to confer R5-tropic resistance to susceptible CD4+T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry.IMPORTANCEHIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4+T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals.

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Trehalose Inhibits Human Immunodeficiency Virus Type 1 Infection in Primary Human Macrophages and CD4+ T Lymphocytes through Two Distinct Mechanisms

Journal of Virology ◽

10.1128/jvi.00237-20 ◽

2020 ◽

Vol 94 (17) ◽

Author(s):

Pratima Rawat ◽

Simson Hon ◽

Carmen Teodorof-Diedrich ◽

Stephen A. Spector

Keyword(s):

T Cells ◽

Hiv Infection ◽

Chemokine Receptor ◽

Viral Entry ◽

Intracellular Replication ◽

Hiv Replication ◽

Human Macrophages ◽

Mechanistic Target Of Rapamycin ◽

Naturally Occurring ◽

Hiv Entry

ABSTRACT Autophagy is a highly conserved recycling pathway that promotes cell survival during periods of stress. We previously reported that induction of autophagy through the inhibition of the mechanistic target of rapamycin (MTOR) inhibits HIV replication in human macrophages and CD4+ T lymphocytes (T cells). However, the inhibition of MTOR has modulatory effects beyond autophagy that might affect viral replication. Here, we examined the effect on HIV replication of trehalose, a nontoxic, nonreducing disaccharide that induces autophagy through an MTOR-independent mechanism. Treatment of HIV-infected macrophages and T cells with trehalose inhibited infection in a dose-dependent manner. Uninfected and HIV-infected macrophages and T cells treated with trehalose exhibited increased markers of autophagy, including LC3B lipidation with further accumulation following bafilomycin A1 treatment, and increased levels of LAMP1, LAMP2, and RAB7 proteins required for lysosomal biogenesis and fusion. Moreover, the inhibition of HIV by trehalose was significantly reduced by knockdown of ATG5. Additionally, trehalose downregulated the expression of C-C motif chemokine receptor 5 (CCR5) in T cells and CD4 in both T cells and macrophages, which reduced HIV entry in these cells. Our data demonstrate that the naturally occurring sugar trehalose at doses safely achieved in humans inhibits HIV through two mechanisms: (i) decreased entry through the downregulation of CCR5 in T cells and decreased CD4 expression in both T cells and macrophages and (ii) degradation of intracellular HIV through the induction of MTOR-independent autophagy. These findings demonstrate that cellular mechanisms can be modulated to inhibit HIV entry and intracellular replication using a naturally occurring, nontoxic sugar. IMPORTANCE Induction of autophagy through inhibition of MTOR has been shown to inhibit HIV replication. However, inhibition of the mechanistic target of rapamycin (MTOR) has cellular effects that may alter HIV infection through other mechanisms. Here, we examined the HIV-inhibitory effects of the MTOR-independent inducer of autophagy, trehalose. Of note, we identified that in addition to the inhibition of the intracellular replication of HIV by autophagy, trehalose decreased viral entry in human primary macrophages and CD4+ T cells through the downregulation of C-C motif chemokine receptor 5 (CCR5) in T cells and CD4 in both T cells and macrophages. Thus, we showed that trehalose uniquely inhibits HIV replication through inhibition of viral entry and intracellular degradation in the two most important target cells for HIV infection.

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The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190717163959 ◽

2019 ◽

Vol 19 (18) ◽

pp. 1650-1675 ◽

Cited By ~ 2

Author(s):

Damoder Reddy Motati ◽

Dilipkumar Uredi ◽

E. Blake Watkins

Keyword(s):

Small Molecule ◽

Viral Entry ◽

Biological Evaluation ◽

New Drugs ◽

Design Synthesis ◽

Mortality And Morbidity ◽

Glycoprotein Gp120 ◽

Hiv Entry ◽

Immunodeficiency Syndrome ◽

Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

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Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽

10.3390/v13050784 ◽

2021 ◽

Vol 13 (5) ◽

pp. 784

Author(s):

Solène Lerolle ◽

Natalia Freitas ◽

François-Loïc Cosset ◽

Vincent Legros

Keyword(s):

Host Cell ◽

Viral Entry ◽

Current Knowledge ◽

Restriction Factors ◽

Antiviral State ◽

Cellular Factors ◽

Pathogenic Viruses ◽

Genome Transcription ◽

Infected Cells ◽

Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

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Trace Elements as Immunoregulators in SARS-CoV-2 and Other Viral Infections

Indian Journal of Clinical Biochemistry ◽

10.1007/s12291-021-00961-6 ◽

2021 ◽

Author(s):

Karthick Dharmalingam ◽

Amandeep Birdi ◽

Sojit Tomo ◽

Karli Sreenivasulu ◽

Jaykaran Charan ◽

...

Keyword(s):

Immune Response ◽

Trace Elements ◽

Viral Entry ◽

Viral Infections ◽

Inhibitory Effect ◽

Antioxidants Activity ◽

Host Immune Responses ◽

Complex Interactions ◽

Downstream Processes

AbstractNutritional deficiency is associated with impaired immunity and increased susceptibility to infections. The complex interactions of trace elements with the macromolecules trigger the effective immune response against the viral diseases. The outcome of various viral infections along with susceptibility is affected by trace elements such as zinc, selenium, iron, copper, etc. due to their immuno-modulatory effects. Available electronic databases have been comprehensively searched for articles published with full text available and with the key words “Trace elements”, “COVID-19”, “Viral Infections” and “Immune Response” (i.e. separately Zn, Se, Fe, Cu, Mn, Mo, Cr, Li, Ni, Co) appearing in the title and abstract. On the basis of available articles we have explored the role of trace elements in viral infections with special reference to COVID-19 and their interactions with the immune system. Zinc, selenium and other trace elements are vital to triggerTH1 cells and cytokine-mediated immune response for substantial production of proinflammatory cytokines. The antiviral activity of some trace elements is attributed to their inhibitory effect on viral entry, replication and other downstream processes. Trace elements having antioxidants activity not only regulate host immune responses, but also modify the viral genome. Adequate dietary intake of trace elements is essential for activation, development, differentiation and numerous functions.

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Nanobiocide Based-Silver Nanomaterials Upon Coronaviruses: Approaches for Preventing Viral Infections

Nanoscale Research Letters ◽

10.1186/s11671-021-03558-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Kamyar Khoshnevisan ◽

Hassan Maleki ◽

Hadi Baharifar

Keyword(s):

Viral Entry ◽

Viral Infections ◽

Respiratory Infections ◽

Antiviral Agents ◽

Long Term Stability ◽

Silver Nanomaterials ◽

Inhibitory Mechanisms ◽

Low Toxicity ◽

Nano Graphene

Abstract The effectiveness of silver nanomaterials (AgNMs), as antiviral agents, has been confirmed in humans against many different types of viruses. Nanobiocides-based AgNMs can be effectively applied to eliminate coronaviruses (CoVs), as the cause of various diseases in animals and humans, particularly the fatal human respiratory infections. Mostly, these NMs act effectively against CoVs, thanks to the NMs’ fundamental anti-viral structures like reactive oxygen species (ROS), and photo-dynamic and photo-thermal abilities. Particularly, the antiviral activity of AgNMs is clarified under three inhibitory mechanisms including viral entry limitation, attachment inhibition, and viral replication limitation. It is believed that nanobiocide with other possible materials such as TiO2, silica and, carbon NMs exclusively nano-graphene materials can emerge as a more effective disinfectant for long-term stability with low toxicity than common disinfectants. Nanobiocides also can be applied for the prevention and treatment of viral infections specifically against COVID-19. Graphic Abstract

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Prisoner health: HIV infection and other blood-borne viral infections

British Journal of Nursing ◽

10.12968/bjon.2011.20.10.605 ◽

2011 ◽

Vol 20 (10) ◽

pp. 605-610 ◽

Cited By ~ 3

Author(s):

Ian Peate

Keyword(s):

Hiv Infection ◽

Viral Infections ◽

Prisoner Health

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Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

10.1101/2020.03.30.20047852 ◽

2020 ◽

Cited By ~ 3

Author(s):

Amr H. Sawalha ◽

Ming Zhao ◽

Patrick Coit ◽

Qianjin Lu

Keyword(s):

Oxidative Stress ◽

Immune Response ◽

Viral Entry ◽

Viral Infections ◽

Severe Disease ◽

Disease Course ◽

Vicious Cycle ◽

Respiratory Complications ◽

Disease Remission ◽

Functional Receptor

SummaryInfection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

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