scholarly journals Naturally Derived Anti-HIV Polysaccharide Peptide (PSP) Triggers a Toll-Like Receptor 4-Dependent Antiviral Immune Response

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Madeline Rodríguez-Valentín ◽  
Sheila López ◽  
Mariela Rivera ◽  
Eddy Ríos-Olivares ◽  
Luis Cubano ◽  
...  
Keyword(s):  
Immune Response ◽  
Drug Targets ◽  
Mononuclear Cells ◽  
Toll Like Receptor ◽  
Viral Inhibition ◽  
Toll Like Receptor 4 ◽  
Peripheral Blood Mononuclear ◽  
Antiviral Immune Response ◽  
Anti Hiv ◽  
Hiv 1

Aim. Intense interest remains in the identification of compounds to reduce human immunodeficiency virus type 1 (HIV-1) replication. Coriolus versicolor’s polysaccharide peptide (PSP) has been demonstrated to possess immunomodulatory properties with the ability to activate an innate immune response through Toll-like receptor 4 (TLR4) showing insignificant toxicity. This study sought to determine the potential use of PSP as an anti-HIV agent and whether its antiviral immune response was TLR4 dependent. Materials and Methods. HIV-1 p24 and anti-HIV chemokine release was assessed in HIV-positive (HIV+) THP1 cells and validated in HIV+ peripheral blood mononuclear cells (PBMCs), to determine PSP antiviral activity. The involvement of TLR4 activation in PSP anti-HIV activity was evaluated by inhibition. Results. PSP showed a promising potential as an anti-HIV agent, by downregulating viral replication and promoting the upregulation of specific antiviral chemokines (RANTES, MIP-1α/β, and SDF-1α) known to block HIV-1 coreceptors in THP1 cells and human PBMCs. PSP produced a 61% viral inhibition after PSP treatment in HIV-1-infected THP1 cells. Additionally, PSP upregulated the expression of TLR4 and TLR4 inhibition led to countereffects in chemokine expression and HIV-1 replication. Conclusion. Taken together, these findings put forward the first evidence that PSP exerts an anti-HIV activity mediated by TLR4 and key antiviral chemokines. Elucidating these new molecular mediators may reveal additional drug targets and open novel therapeutic avenues for HIV-1 infection.

scholarly journals Insight in miRNome of Long-Term Non-Progressors and Elite Controllers Exposes Potential RNAi Role in Restraining HIV-1 Infection

2020 ◽  
Vol 9 (8) ◽  
pp. 2452
Author(s):  
Rubén Ayala-Suárez ◽  
Francisco Díez-Fuertes ◽  
Esther Calonge ◽  
Humberto Erick De La Torre Tarazona ◽  
María Gracia-Ruíz de Alda ◽  
...  
Keyword(s):  
Immune Response ◽  
Mononuclear Cells ◽  
Elite Controllers ◽  
Peripheral Blood Mononuclear ◽  
Extreme Phenotypes ◽  
Blood Mononuclear Cells ◽  
Before And After ◽  
Anti Hiv ◽  
Hiv 1

Long-term non-progressors (LTNP) and elite controllers (EC) represent spontaneous natural models of efficient HIV-1 response in the absence of treatment. The main purposes of this work are to describe the miRNome of HIV-1 infected patients with different extreme phenotypes and identify potentially altered pathways regulated by differentially expressed (DE) miRNAs. The miRNomes from peripheral blood mononuclear cells (PBMCs) of dual phenotype EC-LTNP or LTNP with detectable viremia and HIV-infected patients with typical progression before and after treatment, were obtained through miRNA-Seq and compared among them. The administration of treatment produces 18 DE miRNAs in typical progressors. LTNP condition shows 14 DE miRNA when compared to typical progressors, allowing LTNP phenotype differentiation. A set of four miRNAs: miR-144-3p, miR-18a-5p, miR-451a, and miR-324 is strongly downregulated in LTNP and related to protein regulation as AKT, mTOR, ERK or IKK, involved in immune response pathways. Deregulation of 28 miRNA is observed between EC-LTNP and viremic-LTNP, including previously described anti-HIV miRNAs: miR-29a, associated with LTNP phenotype, and miR-155, targeting different pre-integration complexes such as ADAM10 and TNPO3. A holistic perspective of the changes observed in the miRNome of patients with different phenotypes of HIV-control and non-progression is provided.

scholarly journals BMS-232632, a Highly Potent Human Immunodeficiency Virus Protease Inhibitor That Can Be Used in Combination with Other Available Antiretroviral Agents

2000 ◽  
Vol 44 (8) ◽  
pp. 2093-2099 ◽  
Author(s):  
Brett S. Robinson ◽  
Keith A. Riccardi ◽  
Yi-fei Gong ◽  
Qi Guo ◽  
David A. Stock ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Cytotoxic Effects ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Combination Studies ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC50) of 2.6 to 5.3 nM and an EC90 of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23,000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations.

scholarly journals Identification of Dominant Optimal HLA-B60- and HLA-B61-Restricted Cytotoxic T-Lymphocyte (CTL) Epitopes: Rapid Characterization of CTL Responses by Enzyme-Linked Immunospot Assay

2000 ◽  
Vol 74 (18) ◽  
pp. 8541-8549 ◽  
Author(s):  
Marcus A. Altfeld ◽  
Alicja Trocha ◽  
Robert L. Eldridge ◽  
Eric S. Rosenberg ◽  
Mary N. Phillips ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Peripheral Blood Mononuclear ◽  
Antiviral Immune Response ◽  
Ctl Epitopes ◽  
Hla Class I Molecules ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses play a major role in the antiviral immune response, but the relative contribution of CTL responses restricted by different HLA class I molecules is less well defined. HLA-B60 or the related allele B61 is expressed in 10 to 20% of Caucasoid populations and is even more highly prevalent in Asian populations, but yet no CTL epitopes restricted by these alleles have been defined. Here we report the definition of five novel HLA-B60-restricted HIV-1-specific CTL epitopes, using peripheral blood mononuclear cells in enzyme-linked immunospot (Elispot) assays and using CTL clones and lines in cytolytic assays. The dominant HLA-B60-restricted epitope, Nef peptide KEKGGLEGL, was targeted by all eight subjects with B60 and also by both subjects with B61 studied. This study additionally establishes the utility of the Elispot assay as a more rapid and efficient method of defining novel CTL epitopes. This approach will help to define new CTL epitopes that may play an important role in the immune control of HIV-1.

scholarly journals P1764EXPRESSION OF TOLL-LIKE RECEPTOR 4, BUT NOT THE TOLL-LIKE RECEPTOR 2, MAY BE USEFUL I ASSESING THE RISK OF RENAL TRANSPLANT DETERIORATION IN RECIPIENTS WHO HAVE RECOVERED FROM CYTOMEGALOVIRUS INFECTION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Sławomir Zmonarski ◽  
Mirosław Banasik ◽  
Tomasz Gołębiowski ◽  
Letachowicz Krzysztof ◽  
Joanna Zmonarska ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Cmv Infection ◽  
Toll Like Receptor 4 ◽  
Peripheral Blood Mononuclear ◽  
Data Binding ◽  
Toll Like Receptor 2 ◽  
The Impact

Abstract Background and Aims Data binding the expression of Toll-like (TLR) 4 receptor (TLR4ex), or TLR2 receptor (TLR2ex) and transplanted kidney (KT) function and symptomatic infections with CMV (CMV+) and are scarcely available. Objective: To investigate the relationships between TLR4ex and TLR2ex, a relapse of CMV+ and transplant function. Method Materials and methods: TLR4ex and TLR2ex were measured in peripheral blood mononuclear cells of KT recipients. We compared TLR4ex and TLR2ex among 25 CMV+ patients; 81 patients without CMV infection (CMVn). At the beginning (Day-0) TLR4ex, as well as concentrations of cyclosporin A (CyA) and tacrolimus (TAC) were determined. Both CMV+ and CMVn patients were divided according to the respective median of TLR4ex into groups of low-TLR2/4 expression (L-TLR2/4ex) and high-TLR2/4 expression (H-TLR2/4ex). Glomerular filtration rate (EGFR) was assessed on Day-0 and after the follow-up (F-up). The magnitudes of EGFR change (ΔEGFR) were evaluated. Stable treatment along the F-up period (median 11.9 months) was applied. Results Results. In CMV+ TLR2ex of 64,3% and TLR4ex in 67% is below respective median. Past CMV strongly affected TLR2ex and moderately TLR4ex. On Day-0: in CMV+ we found no link of TLR2 ex and TLR4ex with EGFR; In CMV+ TLR2ex and TLR4ex were lower but Day-0 EGFR did not differ from H-TLR2 or H-TLR4ex. In CMVn: GFR-TLR4ex link was present with no similar in case of GFR-TLR2ex. In patients treated with tacrolimus CMV strongly affected TLR4ex, blurring CMV+/CMVn differences. Post F-up: in CMV+ with L-TLR4ex EGFR declined, there was no change of EGFR in H-TLR4ex; L/H-TLR2ex showed no differences in EGFR. In CMVn with H-TLR4ex EGFR rose, there was no change in L-TLR4ex. In case of TLR2ex we showed no similar differences. Regression analysis points out the impact of CMV+ and TLR4ex on eGFR and ΔEGFR. No similar impact of CMV+ and TLR2ex on eEGFR and ΔEGFR was found. Conclusion Conclusion: In the group who had a symptomatic CMV + infection, low TLR4 expression increases the risk of worsening EGFR. In CMVn, high TLR4 expression increases the chance of EGFR improvement. Historic CMV + strongly affects TLR2ex. However, TLR2ex cannot be used as a factor in assessing the risk of EGFR deterioration.

scholarly journals Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

2013 ◽  
Vol 58 (2) ◽  
pp. 687-697 ◽  
Author(s):  
Ana M. Chamoun-Emanuelli ◽  
Michael Bobardt ◽  
Bernard Moncla ◽  
Marie K. Mankowski ◽  
Roger G. Ptak ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Stability ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Synthetic Compound ◽  
Peripheral Blood Mononuclear ◽  
Simplex Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTPD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672–681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensalLactobacillusspecies (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4+T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans.

scholarly journals Highly Potent Inhibition of Human Immunodeficiency Virus Type 1 Replication by TAK-220, an Orally Bioavailable Small-Molecule CCR5 Antagonist

2005 ◽  
Vol 49 (8) ◽  
pp. 3474-3482 ◽  
Author(s):  
Katsunori Takashima ◽  
Hiroshi Miyake ◽  
Naoyuki Kanzaki ◽  
Yoshihiko Tagawa ◽  
Xin Wang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Host Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT TAK-220 is a member of a novel class of chemokine receptor antagonists and is highly specific to CCR5, as determined by receptor binding and calcium mobilization assays. The compound selectively inhibited coreceptor-mediated entry of human immunodeficiency virus type 1 (HIV-1) into host cells and HIV-1 infection mediated by CCR5. TAK-220 inhibited the replication of six CCR5-using (R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) with a mean 90% effective concentration of 13 nM. The anti-HIV-1 activity of TAK-220 was not affected by addition of high concentrations of human serum. It equally inhibited R5 HIV-1 replication in PBMCs obtained from eight different donors, irrespective of the levels of viral production. Furthermore, the anti-HIV-1 activity of TAK-220 was found to be subtype independent. TAK-220 did not induce CCR5 internalization but blocked the binding of two monoclonal antibodies that recognize the second extracellular loop of CCR5 in CCR5-expressing cells. These results suggest that TAK-220 selectively inhibits R5 HIV-1 replication by interfering with coreceptor-mediated entry of the virus into host cells. At a dose of 5 mg/kg of body weight, TAK-220 showed oral bioavailabilities of 9.5 and 28.9% in rats and monkeys, respectively. Thus, TAK-220 is a promising candidate for the treatment of HIV-1 infection.

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