scholarly journals Mechanism by which the lectin actinohivin blocks HIV infection of target cells

2009 ◽  
Vol 106 (37) ◽  
pp. 15633-15638 ◽  
Author(s):  
Haruo Tanaka ◽  
Harumi Chiba ◽  
Junji Inokoshi ◽  
Atsushi Kuno ◽  
Takahiro Sugai ◽  
...  
Keyword(s):  
Hiv Transmission ◽  
3D Structure ◽  
Target Cells ◽  
Molecular Tools ◽  
Sugar Binding ◽  
Rnase B ◽  
Binding Pockets ◽  
Specific Affinity ◽  
Anti Hiv

Various lectins have attracted attention as potential microbicides to prevent HIV transmission. Their capacity to bind glycoproteins has been suggested as a means to block HIV binding and entry into susceptible cells. The previously undescribed lectin actinohivin (AH), isolated by us from an actinomycete, exhibits potent in vitro anti-HIV activity by binding to high-mannose (Man) type glycans (HMTGs) of gp120, an envelope glycoprotein of HIV. AH contains 114 aa and consists of three segments, all of which need to show high affinity to gp120 for the anti-HIV characteristic. To generate the needed mechanistic understanding of AH binding to HIV in anticipation of seeking approval for human testing as a microbicide, we have used multiple molecular tools to characterize it. AH showed a weak affinity to Manα(1–2)Man, Manα(1–2)Manα(1–2)Man, of HMTG (Man8 or Man9) or RNase B (which has a single HMTG), but exhibited a strong and highly specific affinity (Kd= 3.4 × 10−8M) to gp120 of HIV, which contains multiple Man8 and/or Man9 units. We have compared AH to an alternative lectin, cyanovirin-N, which did not display similar levels of discrimination between high- and low-density HMTGs. X-ray crystal analysis of AH revealed a 3D structure containing three sugar-binding pockets. Thus, the strong specific affinity of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the “cluster effect” of lectin. Thus, AH is a good candidate for investigation as a safe microbicide to help prevent HIV transmission.

scholarly journals Neutrophil extracellular traps from healthy donors and HIV-1-infected individuals restrict HIV-1 production in macrophages

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Andrés Mojoli ◽  
Barbara Simonson Gonçalves ◽  
Jairo R. Temerozo ◽  
Bruno Cister-Alves ◽  
Victor Geddes ◽  
...  
Keyword(s):  
Virus Production ◽  
Significant Inhibition ◽  
Target Cells ◽  
Extracellular Traps ◽  
Healthy Donors ◽  
Activated Neutrophils ◽  
Immunity Mechanism ◽  
Anti Hiv ◽  
Hiv 1

Abstract Neutrophils release extracellular traps (NETs) after interaction with microorganisms and physiological or synthetic products. NETs consist of decondensed chromatin complexed with proteins, some of them with microbicidal properties. Because NETs can modulate the functioning of HIV-1 target cells, we aimed to verify whether they modify HIV-1 replication in macrophages. We found that exposure of HIV-1-infected macrophages to NETs resulted in significant inhibition of viral replication. The NET anti-HIV-1 action was independent of other soluble factors released by the activated neutrophils, but otherwise dependent on the molecular integrity of NETs, since NET-treatment with protease or DNase abolished this effect. NETs induced macrophage production of the anti-HIV-1 β-chemokines Rantes and MIP-1β, and reduced the levels of integrated HIV-1 DNA in the macrophage genome, which may explain the decreased virus production by infected macrophages. Moreover, the residual virions released by NET-treated HIV-1-infected macrophages lost infectivity. In addition, elevated levels of DNA-elastase complexes were detected in the plasma from HIV-1-infected individuals, and neutrophils from these patients released NETs, which also inhibited HIV-1 replication in in vitro infected macrophages. Our results reveal that NETs may function as an innate immunity mechanism able to restrain HIV-1 production in macrophages.

scholarly journals Syndecan-Fc Hybrid Molecule as a Potent In Vitro Microbicidal Anti-HIV-1 Agent

2010 ◽  
Vol 54 (7) ◽  
pp. 2753-2766 ◽  
Author(s):  
Michael D. Bobardt ◽  
Udayan Chatterji ◽  
Lana Schaffer ◽  
Lot de Witte ◽  
Philippe A. Gallay
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Sexual Transmission ◽  
Antiviral Agent ◽  
Target Cells ◽  
Hybrid Molecule ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4+ T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.

scholarly journals Comparative Evaluation of Virus Transmission Inhibition by Dual-Acting Pyrimidinedione Microbicides Using the Microbicide Transmission and Sterilization Assay

2008 ◽  
Vol 52 (8) ◽  
pp. 2787-2796 ◽  
Author(s):  
Karen M. Watson ◽  
Christa E. Buckheit ◽  
Robert W. Buckheit
Keyword(s):  
Cell Culture ◽  
Hiv Transmission ◽  
Virus Transmission ◽  
Virus Production ◽  
In Vitro Assays ◽  
Target Cells ◽  
Vaginal Mucosa ◽  
Immunodeficiency Virus ◽  
Short Time

ABSTRACT In the absence of a fully effective human immunodeficiency virus (HIV) vaccine, topical microbicides represent an important strategy for preventing the transmission of HIV through sexual intercourse, the predominant mode of HIV transmission worldwide. Although a comprehensive understanding of HIV transmission has not yet emerged in the microbicide field, it is likely the result of rapid infection of monocyte-derived cells in the vaginal mucosa by CCR5-tropic viruses. Inhibition of HIV transmission requires agents that prevent entry, fusion, reverse transcription, or other preintegrative replication events or agents which directly inactivate HIV or modulate the target cells to render them uninfectible. In vitro assays typically used to evaluate the ability of a microbicide to prevent virus transmission use epithelial or human osteosarcoma-derived cells or immune cells more relevant to the development of anti-HIV therapeutic agents and quantify virus production at short time intervals following infection. We have developed a microbicide transmission and sterilization assay (MTSA) to more sensitively and quantitatively evaluate virus transmission in cell culture in the presence of microbicidal compounds. Results obtained with the MTSA demonstrate that the inhibitory capacity of microbicides is often overestimated in short-term transmission inhibition assays, while some compounds yield equivalent inhibitory results, indicating a biological relevance for the MTSA-based evaluations to identify superior potent microbicides. The MTSA defines the concentration of the microbicide required to totally suppress the transmission of virus in cell culture and may thus help define the effective concentration of the microbicide required in a formulated microbicide product.

scholarly journals Efficient inhibition of HIV-1 replication in human immature monocyte-derived dendritic cells by purified anti–HIV-1 IgG without induction of maturation

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4466-4474 ◽  
Author(s):  
Vincent Holl ◽  
Maryse Peressin ◽  
Sylvie Schmidt ◽  
Thomas Decoville ◽  
Susan Zolla-Pazner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inhibitory Activity ◽  
Hiv Transmission ◽  
Autologous Blood ◽  
Target Cells ◽  
Hiv Replication ◽  
Cellular Targets ◽  
Immature Dendritic Cells ◽  
Hiv 1

AbstractDuring mucosal HIV transmission, immature dendritic cells (DCs) present in the mucosa are among the first cellular targets of the virus. Previous studies have analyzed the inhibition of HIV-1 transfer from human mature DCs to T lymphocytes by neutralizing IgG, but so far no in vitro data regarding the capacity of antibodies to inhibit HIV-1 infection of immature DCs have been reported. Here, we found an increased HIV-inhibitory activity of monoclonal IgG and purified polyclonal IgG when immature monocyte-derived dendritic cells (iMDDCs) were used as target cells instead of autologous blood lymphocytes. We showed that FcγRII is involved in the mechanism for inhibiting HIV-1 infection of iMDDCs by IgG, whereas no induction of maturation was detected at concentrations of IgG that result in a 90% reduction of HIV replication. After induction of FcγRI expression on iMDDCs by IFN-γ, an augmentation of the HIV-inhibitory activity of IgG, related to the expression of FcγRI, was observed. Taken together, our results demonstrate the participation of FcγRs in HIV-1 inhibition by IgG when iMDDCs are the targets. We propose that IgG is able to efficiently inhibit HIV-1 replication in iMDDCs and should be one of the components to be induced by vaccination.

scholarly journals Development and evaluation of mucoadhesive bigel containing tenofovir and maraviroc for HIV prophylaxis

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Margaret O. Ilomuanya ◽  
Ayotunde T. Hameedat ◽  
Edidiong N Akang ◽  
Sabdat O. Ekama ◽  
Boladale O. Silva ◽  
...  
Keyword(s):  
Release Rate ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Effective Diffusion ◽  
In Vitro Release ◽  
Physicochemical Characteristics ◽  
Transcriptase Inhibitor ◽  
Chamber Volume ◽  
Anti Hiv

Abstract Background Sexual transmission of HIV is the most common means of acquiring the disease. Topical microbicides have been investigated to prevent transmission. This study will use a specific entry inhibitor, maraviroc, and a nucleotide reverse transcriptase inhibitor (NRTI), tenofovir, a dual combination which will provide a synergist effect that can enhance the efficacy of HIV microbicides via a mucoadhesive dual compartment bigel. Bigel formulation via hydrogel organogel linkages were developed and evaluated for their physicochemical characteristics, safety, and anti-HIV efficacy. In vitro diffusion studies were performed with Franz diffusion cells having effective diffusion surface area of 1.76cm2 and receiver chamber volume of 15mL. Result The bigel formulations showed a viscosity ranging from 14179 to 14560 cPs and had a good spreadability and acidic pH in the range of 4.0 ± 0.34 to 5.2 ± 0.18. The bigel formulations showed good anti-HIV activity at a concentration of 0.1 μg/mL. The in vitro release study of maraviroc from the bigel formulations showed a release rate ranging from 2.675 to 3.838 μg/cm2/min½ while the release rate for tenofovir ranged from 3.475 to 3.825 μg/cm2/min½. The bigel formulations were non-toxic to the human vagina as there was < 1 log10 change in Lactobacilli crispatus viability. Conclusion This study successfully developed a dual compartment bigel containing maraviroc and tenofovir. BG C was found to be stable and safe towards vaginal and rectal epithelium, and it actively prevented HIV transmission. This bigel has the potential for long-term pre-exposure prophylaxis prevention of HIV transmission.

scholarly journals Sublimable C5A Delivery Provides Sustained and Prolonged Anti-HIV Microbicidal Activities

2012 ◽  
Vol 56 (6) ◽  
pp. 3336-3343 ◽  
Author(s):  
Richard Maskiewicz ◽  
Michael Bobardt ◽  
Udayan Chatterji ◽  
Simi Gunaseelan ◽  
Charlene S. Dezzutti ◽  
...  
Keyword(s):  
Enzymatic Degradation ◽  
Hiv Transmission ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Helical Peptide ◽  
Moist Environment ◽  
Anti Hiv

ABSTRACTWe have identified a short amphipathic helical peptide, called C5A, which exhibits potent microbicidal activitiesin vitroand which offers protection from vaginal HIV transmissionin vivoin a humanized mouse model. However, there are many obstacles to overcome before C5A can be considered a true microbicidal candidate. First, it must be stabilized against enzymatic degradation in a continuously warm and moist environment. Second, it must be delivered in a controlled manner to achieve long-term and coitally independent efficacy. We demonstrate in thisin vitrostudy that the combination of two matrices with different subliming properties ((hexamethylcyclotrisiloxane [HMCS] and cyclododecane [CDD]) containing 10% labile C5A yielded the best results in terms of controlled release and preserved anti-HIV activity of the peptide when pre-exposed to cell-free medium or cell culture at body temperature for up to 2 months.

Target Molecules and Delivery Vehicles for Anti-HIV Drugs In vitro and In vivo

2018 ◽  
Vol 24 (29) ◽  
pp. 3393-3401 ◽  
Author(s):  
Azam Bolhassani
Keyword(s):  
Drug Targeting ◽  
Immune Deficiency Syndrome ◽  
Antiretroviral Drugs ◽  
Host Cells ◽  
Target Cells ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

Acquired Immune Deficiency Syndrome (AIDS) is the most serious stage of Human Immunodeficiency Virus (HIV) infection. The combinatorial Anti-Retroviral Therapy (cART) is widely used in suppressing HIV-1 infection and enhancing life span of infected patients to a significant level. However, delivery of therapeutic molecules is still a major challenge in vivo. The studies showed that the anti-HIV drugs delivered via nanocarriers could be selectively accumulated in infected cells accompanied by low side effects. On the other hand, HIV-1 infection kinetics is different in macrophages and T-cells suggesting various effects of antiretroviral drugs against HIV-1 in these target cells. Current anti-HIV therapeutic studies have focused on developing drug delivery systems targeted specifically to HIV-infected host cells. Indeed, the drug targeting can significantly lead to reduce in drug toxicity, drug dose, and increase in treatment efficacy through localizing its pharmacological activity to the site of interest. This review describes development of novel drug targeting systems used in suppressing the transmission and treatment of HIV infections.

Ultrastructural Changes in Tumor Cells During Human Peripheral Blood Monocyte-Mediated Cytotoxicity

1981 ◽  
Vol 39 ◽  
pp. 452-453
Author(s):  
K. E. Muse ◽  
D. G. Fischer ◽  
H. S. Koren
Keyword(s):  
Target Cell ◽  
Human Peripheral Blood ◽  
Mononuclear Phagocytes ◽  
Ultrastructural Changes ◽  
Target Cells ◽  
Limited Information ◽  
Blood Monocytes ◽  
Tumoricidal Activity ◽  
Activated State

Mononuclear phagocytes, a pluripotential cell line, manifest an array of basic extracellular functions. Among these physiological regulatory functions is the expression of spontaneous cytolytic potential against tumor cell targets.The limited observations on human cells, almost exclusively blood monocytes, initially reported limited or a lack of tumoricidal activity in the absence of antibody. More recently, freshly obtained monocytes have been reported to spontaneously impair the biability of tumor target cells in vitro (Harowitz et al., 1979; Montavani et al., 1979; Hammerstrom, 1979). Although the mechanism by which effector cells express cytotoxicity is poorly understood, discrete steps can be distinguished in the process of cell mediated cytotoxicity: recognition and binding of effector to target cells,a lethal-hit stage, and subsequent lysis of the target cell. Other important parameters in monocyte-mediated cytotoxicity include, activated state of the monocyte, effector cell concentrations, and target cell suseptibility. However, limited information is available with regard to the ultrastructural changes accompanying monocyte-mediated cytotoxicity.

STEROID HORMONE METABOLISM IN RESPONSIVE TISSUES IN VITRO

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S279-S294 ◽  
Author(s):  
Paul Robel
Keyword(s):  
Steroid Hormone ◽  
Physiological Activity ◽  
Physiological State ◽  
Target Cells ◽  
Target Tissue ◽  
Hormone Metabolism ◽  
Metabolizing Enzymes ◽  
Relationship Of

ABSTRACT Of the information available on steroid hormone metabolism in responsive tissues, only that relating hormone metabolism to physiological activity is reviewed, i. e. metabolite activity in isolated in vitro systems, binding of metabolites to target tissue receptors, specific steroid hormone metabolizing enzymes and relationship of hormone metabolism to target organ physiological state. Further, evidence is presented in the androgen field, demonstrating 5α-reduced metabolites, formed inside the target cells, as active compounds. This has led to a consideration of testosterone as a »prehormone«. The possibility that similar events take place in tissues responding to progesterone is discussed. Finally, the role of hormone metabolism in the regulation of hormone availability and/or renewal in target cells is discussed. In this context, reference is made to the potential role of plasma binding proteins and cytosol receptors.

Anti HIV-1 Agents 7. Discovery of 1-Hydroxy-4-chloro-9,10-anthraquinone Derivatives as New HIV-1 Inhibitors in Vitro

2011 ◽  
Vol 8 (7) ◽  
pp. 602-605
Author(s):  
Ning Huang ◽  
Qin Wang ◽  
Liu-Meng Yang ◽  
Hui Xu ◽  
Yong-Tang Zheng
Keyword(s):  
Anthraquinone Derivatives ◽  
Anti Hiv ◽  
Hiv 1
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