Publications by authors named "Rouhollah Vahabpour"

44 Publications

Piroxicam Analogs: Design, Synthesis, Docking Study and Biological Evaluation as Promising Anti-HIV-1 agents.

Med Chem 2021 Jan 25. Epub 2021 Jan 25.

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran. Iran.

Background: Taking the well-known drug, Piroxicam as a lead compound, we designed and synthesized two series of 1,2-benzothiazines 1,1-dioxide derivatives to assay their ability in inhibition of HIV-1 replication in cell culture.

Objective: In this study, we describe the synthesis, docking study and biological evaluation of 1,2-benzothiazines 1,1- dioxide derivatives.

Results: Most of the new compounds were active in the cell-based anti-HIV-1 assay with EC50 < 50 M. Among them, compounds 7g was found to be the most active molecule. Docking study using 3OYA pdb code on the most active molecule 7g with EC50 values of 10 M showed a similar binding mode to the HIV integrase inhibitors.

Conclusion: Since all the compounds showed no remarkable cytotoxicity (CC50> 500 M), the designed scaffold is promising structure for development of new anti-HIV-1 agents.
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http://dx.doi.org/10.2174/1573406417666210125141639DOI Listing
January 2021

Anti-HIV-1 Activity of the Recombinant HIV-1 TAT Protein Along With Tenofovir Drug.

Curr HIV Res 2021 ;19(2):138-146

Department of Hepatitis, AIDS and Blood Borne Diseases, Pasteur Institute of Iran, Tehran, Iran.

Background: HIV-1 TAT protein is essential for the regulation of viral genome transcription. The first exon of TAT protein has a fundamental role in the stimulation of the extrinsic and intrinsic apoptosis pathways, but its anti-HIV activity is not clear yet.

Methods: In the current study, we firstly cloned the first exon of the TAT coding sequence in the pET-24a expression vector and then protein expression was done in the Rosetta expression host. Next, the expressed TAT protein was purified by Ni-NTA column under native conditions. After that, the protein yield was determined by Bradford kit and NanoDrop spectrophotometry. Finally, the cytotoxicity effect and anti-Scr-HIV-1 activity of the recombinant TAT protein alone and along with Tenofovir drug were assessed by MTT and ELISA, respectively.

Results: The recombinant TAT protein was successfully generated in E. , as confirmed by 13.5% SDS-PAGE and western blotting. The protein yield was ~150-200 μg/ml. In addition, the recombinant TAT protein at a certain dose with low toxicity could suppress Scr-HIV replication in the infected HeLa cells (~30%) that was comparable with a low toxic dose of Tenofovir drug (~40%). It was interesting that the recombinant TAT protein could enhance anti-HIV potency of Tenofovir drug up to 66%.

Conclusion: Generally, a combination of TAT protein and Tenofovir drug could significantly inhibit HIV-1 replication. It will be required to determine their mechanism of action in the next studies.
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http://dx.doi.org/10.2174/1570162X18666201012152600DOI Listing
January 2021

Novel 4-Oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic Acid Derivatives as HIV-1 Integrase Inhibitors: Synthesis, Docking studies, Molecular Dynamics Simulation and Biological Activities.

Med Chem 2020 Sep 8. Epub 2020 Sep 8.

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran. Iran.

Background: HIV-1 integrase (IN) has been considered as an important target for the development of novel antiHIV-1 drugs.

Objective: The aim of study is to design a novel groups of HIV IN inhibitors.

Method: In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole -diketoacids as a well-known group of IN inhibitors.

Results: Based on in-vitro anti-HIV-1 activity in cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC50 values of 4.14, 1.68 and 0.8 M, respectively. However, integrase inhibition assay showed that most of analogues did not have significant effects against integrase enzyme except compound 5 with IC50 value of 45 M. Our results indicated that compound 6k was the best one among synthesized compounds with an EC50 of 0.8 M and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into probable mechanism of tested compounds.

Conclusion: These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives may consider as promising lead compounds for development of new anti-HIV-1 drugs.
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http://dx.doi.org/10.2174/1573406416666200909104616DOI Listing
September 2020

Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-Arylidene-pyrido [2,3-]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents.

Iran J Pharm Res 2019 ;18(Suppl1):237-248

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In an attempt to identify potential new agents that are active against HIV-1, a series of novel pyridopyrimidine-5-carbohydrazide derivatives featuring a substituted benzylidene fragment were designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors. The cytotoxicity profiles of these compounds showed no significant toxicity to human cells and they exhibited anti-HIV-1 activity with EC50 values ranging from 90 to 155 µM. Compound 5j bearing 4-methylbenzylidene group was found to be the most active compound with EC50 = 90 µM and selectivity index, CC50/EC50 = 6.4. Molecular modeling studies indicated the capacity of compound 5j to interact with two Mg2+ cations and several residues that are important in HIV-1 integrase inhibition. These findings suggested that pyridopyrimidine-5-carbohydrazide scaffold might become a promising template for development of novel anti-HIV-1 agents.
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http://dx.doi.org/10.22037/ijpr.2019.112198.13597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393058PMC
January 2019

Design, Synthesis, Molecular Modeling Studies and Biological Evaluation of N'-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide Derivatives as Novel Anti-HCV Agents.

Iran J Pharm Res 2019 ;18(4):1790-1802

Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

HCV-induced hepatitis is one of the most debilitating diseases. The limited number of anti-HCV drugs and drug-resistance necessitate developing of new scaffolds with different mode of actions. HCV non-structural protein 5B (NS5B) is an attractive target for development of novel inhibitors of HCV replication. In this paper, new N'-arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives were designed based on the pharmacophores of HCV NS5B active site binding inhibitors. Designed compounds were synthesized and evaluated for their inhibitory activities in a cell-based HCV replicon system assay. Among tested compounds, compounds and were found to be the most active (EC = 35 and 70 µM, respectively) with good selectivity index (SI > 2) in the corresponding series. Molecular modeling studies showed that the designed compounds are capable of forming key coordination with the two magnesium ions as well as interactions with other key residues at the active site of HCV NS5B.
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http://dx.doi.org/10.22037/ijpr.2019.112186.13586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059030PMC
January 2019

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives.

Curr HIV Res 2020 ;18(1):41-51

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle.

Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV.

Methods: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-component reaction from 3-amino-4-hydroxycoumarin, isatoic anhydride and benzaldehyde derivatives.

Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well.

Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.
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http://dx.doi.org/10.2174/1570162X17666191210105809DOI Listing
January 2020

Design, synthesis and evaluation of cytotoxic, antimicrobial, and anti-HIV-1 activities of new 1,2,3,4-tetrahydropyrimidine derivatives.

Res Pharm Sci 2019 Apr 8;14(2):155-166. Epub 2019 Mar 8.

Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, I.R. Iran.

A series of new 1,2,3,4-tetrahydropyrimidine (THPM) derivatives were designed and synthesized within a one-pot three component Biginelli reaction. The structures of compounds were characterized by FT-IR, 1HNMR, mass spectroscopy, and elemental analysis. All synthesized derivatives were screened for their cytotoxic, antimicrobial, and anti-HIV activities. Due to significant cytotoxic and antimicrobial effects of 1,2,3,4-THPM scaffold, in this study, cytotoxic and antimicrobial activities of synthesized derivatives were evaluated on two cell lines and four bacterial strains. Compounds and showed highest cytotoxic activity against HeLa and MCF-7 cell lines. In addition, and were most active against MCF-7 and HeLa cell lines, respectively. Among the compounds, revealed high antimicrobial activity against four strains. According to the results, 4e possessing -bromophenyl group at C-4 position of THPM exhibited the highest cytotoxic and antimicrobial effects. Also, all the newly synthesized compounds were evaluated for their anti-HIV-1 assay. Compounds and indicated remarkable anti-HIV-1 activity. It is concluded from cytotoxic, antimicrobial, and anti-HIV-1 activities that the 1,2,3,4-tertahydropyrimidines may serve as hit compounds for development of new anticancer small-molecules.
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http://dx.doi.org/10.4103/1735-5362.253363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791171PMC
April 2019

Novel Benzoxazin-3-one Derivatives: Design, Synthesis, Molecular Modeling, Anti-HIV-1 and Integrase Inhibitory Assay.

Med Chem 2020 ;16(7):938-946

Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Integrase is a validated drug target for anti-HIV-1 therapy. The second generation integrase inhibitors display π-stacking interaction ability with 3'-end nucleotide as a streamlined metal chelating pharmacophore.

Methods: In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisostere replacement strategy of 2-benzoxazolinone.

Results: Molecular modeling studies revealed that amide functionality alongside oxadiazole heteroatoms and sulfur in the second position of oxadiazole ring could mimic the metal chelating pharmacophore. The halobenzyl ring occupies hydrophobic site created by the cytidylate nucleotide (DC-16).

Conclusion: The most potent and selective compound displayed 110 μM IC50 with a selectivity index of more than 2.
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http://dx.doi.org/10.2174/1573406415666190826161123DOI Listing
January 2020

Anti-viral Effects of Superpositively Charged Mutant of Green Fluorescent Protein.

Protein Pept Lett 2019 ;26(12):930-939

Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.

Background: Supercharged GFP proteins were known as effective carriers for delivery of macromolecules into eukaryotic cells as well as fluorescent fusion tags for in vitro and in vivo detection.

Objective: Herein, anti-viral effects of +36 GFP and its anti-tumor effects were studied in vitro and in vivo, respectively.

Methods: We evaluated anti-HIV, anti-HSV, and anti-HCV effects of +36 GFP in vitro using ELISA, and real time PCR as common techniques for their detection, respectively. Moreover, we assessed the role of +36 GFP for eliciting HPV-related anti-tumor effects in mice due to the lack of HPV replication in vitro.

Results: Our data showed that +36 GFP efficiently enter the cells and augment the transfection rate of HPV16E7 antigen, as well. Furthermore, +36 GFP significantly reduced HCV, HIV and HSV replication up to 75%, 49% and 43% in HCV-infected Huh7.5 cells, HIV-infected Hela cells and HSV-infected Vero cells, respectively. On the other hand, mice immunization with +36 GFP complexed with HPV16 E7 antigen (+36GFP + E7) or fused to HPV16 E7 antigen (+36GFP-E7) elicited a higher Th1 cellular immune response with the predominant IgG2a, IgG2b, IFN-γ and Granzyme B levels than those induced by other groups. These regimens protected mice against TC- 1 tumor challenge (~ 67%) compared to E7 protein alone (~ 33%). These data suggested that +36 GFP can act as an anti-viral agent at certain dose due to its high efficiency in cell penetration in vitro and in vivo.

Conclusion: Generally, +36 GFP targets viral replication in vitro as well as helps to suppress the growth of HPV-related tumors in vivo.
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http://dx.doi.org/10.2174/0929866526666190823145916DOI Listing
January 2020

In Vitro Anti-Viral Effects of Small Heat Shock Proteins 20 and 27: A Novel Therapeutic Approach.

Curr Pharm Biotechnol 2019 ;20(12):1011-1017

Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.

Background: The protective effects of heat shock proteins (Hsps) were studied in some infectious and non-infectious diseases, but their specificity was slightly known in various disorders. Among Hsps, small Hsps (e.g. Hsp27 and Hsp20) have important roles in protein folding and translocation, and also in immunity.

Methods: In this study, overexpression of Hsp20 and Hsp27 was performed by transfection of the plasmids encoding Hsp20 and Hsp27 (pEGFP-Hsp20 and pEGFP-Hsp27) into Huh7.5, Hela and Vero cells using Lipofectamine along with heat shock. Then, their anti-herpes simplex virus-1 (HSV-1), anti- human immunodeficiency virus-1 (HIV-1) and anti-hepatitis C virus (HCV) effects, as well as cytotoxicity, were evaluated in vitro, for the first time.

Results: Our data showed that simultaneous treatment with Lipofectamine and heat shock augmented the rate of transfection and subsequently the expression of Hsps in these cells. Moreover, overexpression of Hsp20 in HCV-infected Huh7.5 cells, HIV-infected Hela cells and HSV-infected Vero cells reduced the replication of HCV, HIV and HSV, respectively. In contrast, overexpression of Hsp27 significantly decreased HSV replication similar to Hsp20, but it did not affect the replication of HIV and HCV.

Conclusion: Generally, Hsp20 was identified as a novel anti-HCV, anti-HSV and anti-HIV agent, but Hsp27 was efficient in the suppression of HSV infection. These Hsps may act through suppression of virus entry and/ or through interaction with viral proteins. Thus, it is necessary to determine their exact mechanisms in the near future.
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http://dx.doi.org/10.2174/1389201020666190729104648DOI Listing
January 2020

Rabies Prophylaxis Strategy in Iran, a Need for an Alternative Strategy: Would the Essen Regimen be Replaced by Zagreb Protocol?

Clin Lab 2019 Jan;65(1)

Background: Rabies is a fatal zoonotic infectious disease, which can be prevented by prompt post-exposure prophylaxis that could be expensive in countries with a large population. The Essen protocol with injection of 5 single doses of human rabies vaccine on separate days is a well-known rabies prophylaxis schedule. Decreasing the number of vaccine doses and the number of clinical visits due to an effective alternative schedule is strongly needed. The 2-1-1 regimen, known as Zagreb, is one of the best candidates to succeed Essen.

Methods: To evaluate the effectiveness of Zagreb regimen in the Iranian population by using the Purified Vero cell Rabies Vaccine (PVRV), anti-rabies antibody titer was measured in volunteers with second and third exposure through Rapid Fluorescent Focus Inhibition Test (RFFIT) and Enzyme Linked Immunosorbent Assay (ELISA) test and compared with patients, who were treated according to the Essen protocol.

Results: In all participants, anti-rabies antibody titer reached the protective level with no suppressive effect of rabies immunoglobulin in patients with third exposure in Zagreb regimen.

Conclusions: Zagreb regimen could be considered a suitable alternative for the Essen protocol.
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http://dx.doi.org/10.7754/Clin.Lab.2018.180619DOI Listing
January 2019

Optimization of chitosan nanoparticles as an anti-HIV siRNA delivery vehicle.

Int J Biol Macromol 2019 May 6;129:305-315. Epub 2019 Feb 6.

Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Chitosan has emerged as a promising polysaccharide for gene/siRNA delivery. However, additional works will be required to modify chitosan nanoparticles. In the present study, chitosan nanoparticles were well modified to introduce anti-HIV siRNA into two mammalian cell lines, macrophage RAW 264.7 and HEK293. We first generated two stable cell lines expressing HIV-1 Tat, and then designed and generated an efficient anti-tat siRNA. The nanoparticles were prepared by using different concentrations of chitosan, polyethylenimine (PEI) and carboxymethyl dextran (CMD) in various formulations and then their physicochemical and biological properties were investigated. The results demonstrated that the combination of chitosan with both CMD and PEI significantly improved both cell viability and siRNA delivery. The modified chitosan nanoparticles (ChNPs) at the N:P ratio of 50 were approximately uniform spheres with sizes ranging from 100 to 150 nm and a positive zeta potential of about +22 mV. In both cell types, the nanoparticles noticeably increased siRNA delivery efficiency with no significant cytotoxicity or apoptosis-inducing effects compared to the control cells. In addition, the nanoparticles significantly reduced the RNA and protein expression of HIV-1 tat in both stable cells. These data show that the nanoparticle formulation could potentially be used in gene therapy, especially against HIV infection.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.02.036DOI Listing
May 2019

Long non-coding RNA LY86-AS1 and HCG27_201 expression in type 2 diabetes mellitus.

Mol Biol Rep 2018 Dec 16;45(6):2601-2608. Epub 2018 Oct 16.

Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Long non-coding RNAs (LncRNAs) are non-coding RNAs. The potential roles of lncRNAs in type 2 diabetes mellitus (T2DM) are not well-known. In this study, we aim to assess the expression levels of LY86-AS1 and HCG27_201 in T2DM patients and a healthy control group. We obtained whole blood and serum samples from 100 T2DM and 100 non-diabetic subjects. Peripheral blood mononuclear cells (PBMCs) were extracted from whole blood samples using Ficoll. Total RNA was isolated from PBMCs obtained from patients with type 2 diabetes mellitus and healthy control individuals using TRIzol LS reagent (GeneAll Biotechnology Co., LTD.). Extracted RNA was used to synthesize complementary DNA (cDNA) with a Reverse Transcription Kit (Takara). Real-time was performed with SYBR Green (Takara) and monitored by a Rotor-Gene (Qiagen) system. We performed quantitative PCR analysis of the LY86-AS1 and HCG27_201 lncRNA expression levels in the 200 samples. Here we found that the expression of LY86-AS1 and HCG27_201 were down regulated in the T2DM group compared with the control group. We further identify that the expression of both lncRNAs was negatively correlated with fasting blood sugar (FBS) levels. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of LY86-AS1 and HCG27_201 as biomarkers for T2DM. ROC analysis demonstrated that LY86-AS1 with an area under the ROC curve (AUC) of 0.747 (P < 0.0001, sensitivity: 64.6, and specificity: 79.8) might be the potential novel diagnostic biomarkers for T2DM. Lower expression of our two studied long non-coding RNAs LY86-AS1 and HCG27_201 in type 2 diabetes mellitus patients indicates their role in the pathogenesis of T2DM. Furthermore, LY86-AS1 could possibly be used as a diagnostic marker for T2DM.
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http://dx.doi.org/10.1007/s11033-018-4429-8DOI Listing
December 2018

Downregulation of long non-coding RNAs LINC00523 and LINC00994 in type 2 diabetes in an Iranian cohort.

Mol Biol Rep 2018 Oct 24;45(5):1227-1233. Epub 2018 Jul 24.

Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Long non-coding RNAs (lncRNAs) are a subclass within the non-coding RNA repertoire that have potential roles in type 2 diabetes mellitus (T2DM). However, the biological function and molecular mechanisms of lncRNAs in T2DM remain largely unknown. The purpose of this study is to investigate the association between LINC00523 and LINC00994 expressions and T2DM susceptibility in an Iranian cohort. In this case-control study, we obtained whole blood and serum samples from 100 T2DM patients and 100 healthy subjects. We extracted peripheral blood mononuclear cells (PBMCs) from whole blood samples using Ficoll-Hypaque density-gradient centrifugation. Total RNA was extracted from the PBMC lysates by using the TRIzol-LS reagent (GeneAll). Finally, a quantitative real-time PCR (qPCR) assay was used to detect LINC00523 and LINC00994 lncRNA expression levels in the 200 samples. LINC00523 and LINC00994 expressions significantly decreased in patients with T2DM compared to the healthy participants, with a fold change for LINC00523 of 0.157 and 0.159 for LINC00994. We observed a significant inverse correlation between the expressions of these lncRNAs with FBS. Receiver operating characteristic (ROC) curve analysis revealed that LINC00523 has a higher area under the ROC curve (AUC) of 0.7430 and a lower P-value (P < 0.0001), in addition to a sensitivity of 81.44% and specificity of 61.11%. Therefore, LINC00523 could be considered a potential diagnostic biomarker for T2DM. Decreased expressions of LncRNAs LINC00523 and LINC00994 in T2DM is possibly associated with pathogenicity of T2DM in Iranian population. Moreover, LINC00523 can perhaps be considered as effective diagnostic biomarkers for T2DM.
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http://dx.doi.org/10.1007/s11033-018-4276-7DOI Listing
October 2018

ZnO Q-dots as a potent therapeutic nanomedicine for in vitro cytotoxicity evaluation of mouth KB44, breast MCF7, colon HT29 and HeLa cancer cell lines, mouse ear swelling tests in vivo and its side effects using the animal model.

Artif Cells Nanomed Biotechnol 2018 22;46(sup2):96-111. Epub 2018 Mar 22.

j Barij Essence Pharmaceutical Company , Mashhad Ardehal Kashan , Iran.

Nanoformulations derived from fine porous ZnO quantum dot nanoparticles (QD NPs) can offer strong potential medical applications; especially in cancer therapy. ZnO QD NPs was synthesized by sol-gel hydrothermal process, fast cold quenching and further smart surface functionalization methods to obtain ultrasmall size (1-4 nm) NPs. ZnO nanopolymer, a wetting agent, PEG co-solvent and water/oil emulsion stabilizer were considered in our nanofluid formulation. The resulting nanofluid was characterized by SEM, FTIR, photoluminescence, band gap energy, zeta potential and UV-Vis spectroscopy. The cytotoxic effects on the growth of four cancer cell lines were evaluated by MTT assay. The IC (µg/ml) values of 30, 41, 40 and 35 for KB44, MCF-7, HT29 and HeLa cells, respectively, after 48 h of nanoformulation treatment suggested the cytotoxic effect of this nanoformulation on these cell lines in a concentration-dependent manner (p < .05). ZnO nanofluid destroyed cancer cell lines more efficiently than the normal HFF-2 (IC= 105 µg/ml). The reduction in cell viability in response to ZnO nanofluid treatment induced apoptosis in the cultured cells. Skin sensitization test plus antibacterial activity were also measured. Side effect tests on 70 white mice in vivo resulted in only 3-4 abnormal situations in hepatic tissue section possibly due to the idiosyncratic drug reactions.
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http://dx.doi.org/10.1080/21691401.2018.1452023DOI Listing
June 2019

Truncated JFH1 E2 Protein: Is it Reliable to be Used in Diagnostic ELISA Test and as a Protein-Based Vaccine Candidate?

Protein Pept Lett 2018 Feb;24(12):1179-1184

School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background: HCV E2 glycoprotein is one of the most attractive proteins for designing an effective vaccine. Deletion of hydrophobic carboxyl-terminal region of this protein is necessary for its secretion, especially when it is expressed in E-coli. In this study we expressed this protein in truncated form and evaluated its application in developing an ELISA test and induction of humoral response in immunized mice.

Objectives: The purpose of this study was expression of HCV truncated E2 protein from JFH1 strain in E-coli BL21(DE3) and evaluation of its antigenicity.

Methods: Truncated E2 region from HCV genotype 2a (JFH1) was amplified by PCR and cloned into a pET28a (+) vector and was used to transform the E-coli DH5α strain. The recombinant E2 protein was evaluated both in an ELISA test and induction of humoral immunity in mice.

Results: Truncated E2 protein was expressed in BL21(DE3). Its specific antibody was detected in serum samples from HCV infected patients. Also, it could elicit a significant humoral immunity in mice.

Conclusion: Truncated form of E2 protein which has been expressed in E-coli could be used as an effective antigen both in diagnostic tests such as ELISA and also, as a protein-based vaccine candidate.
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http://dx.doi.org/10.2174/0929866524666171009164314DOI Listing
February 2018

Generation of the Fluorescent HMGB1-GFP Fusion Protein in Insect Cells and Evaluation of its Immunogenicity in Two Mice Models.

Protein Pept Lett 2017 ;24(6):545-550

Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.

Background: High mobility group box 1 (HMGB1) is a highly conserved protein present in the nuclei and cytoplasm of cells which has an important role as a mediator of inflammation in the extracellular environment. HMGB1 was identified as an innate adjuvant that induces immune responses against soluble antigens in vivo.

Objective: Our goal is the generation of recombinant HMGB1-GFP fusion protein in insect cells for evaluation of immune responses in mouse model.

Method: In the current study, we used a baculovirus expression system for insect cells that was based on expression of HMGB1 with target gene (GFP), and purified the recombinant HMGB1- GFP fusion protein. We then demonstrated whether immunogenicity of GFP changes in the presence or absence of recombinant HMGB1 acting as an adjuvant in C57BL/6 and BALB/c mice.

Results: Our data showed that HMGB1 had a major influence on antibody immune responses induced by GFP in both animal models. The groups receiving HMGB1-GFP fusion protein showed total IgG and IgG2a responses significantly higher than IgG1 in BALB/c mice. Indeed, a mixed IgG1/IgG2a response was observed with high intensity toward IgG2a. In contrast, C57BL/6 mice immunized by HMGB1-GFP protein elicited the same levels of IgG1 and IgG2a. However, the levels of IgG2a and total IgG against the recombinant GFP (rGFP) in C57BL/6 mice were lower than those in BALB/c mice.

Conclusion: We concluded that fusion of HMGB1 with GFP was immunologically more effective than GFP alone.
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http://dx.doi.org/10.2174/0929866524666170404161649DOI Listing
October 2017

HIV-1 genetic diversity and transmitted drug resistance frequency among Iranian treatment-naive, sexually infected individuals.

Arch Virol 2017 Jun 8;162(6):1477-1485. Epub 2017 Feb 8.

Department of Virology, Iran University of Medical Sciences, Tehran, Iran.

In recent years, the patterns of human immunodeficiency virus 1 (HIV-1) transmission in Iran have been changing gradually from drug injection to unprotected sexual contact. This study sought to investigate the phylogenetic trends and characteristics of transmitted drug resistance (TDR) mutations of HIV-1 in a population that is mainly infected through homo/heterosexual contacts. Sixty newly diagnosed antiretroviral-naive individuals with HIV infection living in Tehran were recruited to this survey, and among them, 42 subjects were established to be infected through sexual intercourse. Following amplification and sequencing of the main part of the HIV-1 pol region, phylogenetic and drug-resistance mutation (DRM) analysis was successfully performed on these 42 patients. Phylogenetic analysis showed that the majority of the subjects were infected with subtype CRF35_AD (88%), followed by subtype B, with 7.1%, and subtype CRF01_AE, with 4.7%. A total of 7.1% of the subjects were found to be infected with HIV-1 variants with surveillance drug-resistant mutations (SDRMs) according to the last world health organisation (WHO) algorithm. All of the identified SDRMs belonged to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) class, including K103 N and V106A, which were found in three patients. Two minor HIV protease-inhibitor-related mutations (L10I and G73S) were detected in two patients, but these mutations are not included in the WHO SDRMs list. The dominance of HIV-1 subtype CRF35_AD was observed among subjects of this study who were infected through sexual contact. The moderate prevalence of SDRMs (7.1%) in this population emphasises the fact that the risk of treatment failure in HIV-infected individuals might increase in the future, and preventive measures should be considered by health authorities.
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http://dx.doi.org/10.1007/s00705-017-3228-1DOI Listing
June 2017

Expression of HCV Alternative Reading Frame Protein (Core+1/F) in Baculovirus Expression System and its Evaluation for Assessment of Specific Anti-core+1 Antibody in Iranian HCV Infected Patients.

Clin Lab 2016 Oct;62(10):1919-1926

Background: Hepatitis C virus (HCV) genome contains an overlapping reading frame which results in alternative core protein (ARFP). Baculovirus expression system was used as a powerful eukaryotic vector system to express core+1/F protein for the first time. This recombinant core+1/F protein was used to assess the anti-core+1 antibody in anti-HCV drug resistant and sustained virologic response (SVR) patients.

Methods: The core+1 coding sequence from HCV genotype 1 was designed and synthesized in pUC57 vector. It was subcloned into baculovirus donor plasmid pFastBacTM HTA and transposed into baculovirus shuttle vector (bacmid) to transfect Sf9 cells. Recombinant core+1 protein was purified using Ni-NTA agarose under native condition and verified using SDS-PAGE electrophoresis and Western blotting. An enzyme-linked immunosorbent assay (ELISA) was developed using this purified protein to assess anti-core+1 antibody in 28 anti-HCV drug resistant patients and in 34 patients with sustained virologic response (SVR) in comparison with 31 healthy volunteers used as the negative control.

Results: Expression of HCV core+1 protein in Sf9 cells was confirmed by using SDS-PAGE and Western blotting. Antibody titer against core+1 protein in anti-HCV drug resistant patients was significantly higher than that in both the healthy volunteers and SVR patients (p < 0.0001).

Conclusions: HCV core+1 protein was expressed successfully in a baculovirus expression system in high yield in order to develop an ELISA to assess the anti-core+1 antibody. Further studies are needed to reveal the potential application of core+1 protein in anti-HCV treatment prognosis.
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http://dx.doi.org/10.7754/Clin.Lab.2016.160205DOI Listing
October 2016

Autophagy induction reduces telomerase activity in HeLa cells.

Mech Ageing Dev 2017 04 30;163:40-45. Epub 2016 Dec 30.

Hepatitis and AIDS Dept., Pasteur Institute of Iran, Tehran, Iran. Electronic address:

Autophagy is a cellular homeostatic process whereby damaged proteins and organelles are encapsulated into double membrane vesicles, called autophagosomes, for lysosomal digestion. Beclin1 plays a key role in the initial steps of autophagosome formation. In this study, we evaluated the effect of Beclin 1 overexpression in induction of autophagy and the relationship between autophagy induction and telomerase activity in HeLa cells. We found that overexpression of Beclin 1 in HeLa cells leads to autophagosome formation as shown by intracellular autophagosomal marker LC3-II staining. Expression of Beclin1 reduced telomerase activity for about 100 fold compared with the control while it did not affect TERT expression level. The results of cell cycle analysis indicated that the cell cycle and proliferation progressed normally up to 48h post-transfection. Understanding the role of autophagy induction and telomerase in the pathophysiology of aging and human cancer reveal new strategies that hold much promise for intervention and therapeutic uses.
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http://dx.doi.org/10.1016/j.mad.2016.12.011DOI Listing
April 2017

Merkel cell polyomavirus IgG antibody levels are associated with progression to AIDS among HIV-infected individuals.

Arch Virol 2017 Apr 20;162(4):963-969. Epub 2016 Dec 20.

Department of Virology, Iran University of Medical Sciences, Junction of Shahid Hemmat and Shahid Chamran Expressways, P.O. Box: 15785-6171, Tehran, 1449614535, Iran.

The association of Merkel cell polyomavirus (MCPV) with Merkel cell carcinoma (MCC) in immunocompromised individuals has been revealed in a number of surveys. The study of MCPV specific antibody titers and viral loads in such patients has a great attraction for research groups interested in viral reactivation. In this cross-sectional study to evaluate MCPV antibody titer, DNA prevalence and viral load in peripheral blood mononuclear cells (PBMCs), we examined 205 HIV-1 infected patients and 100 un-infected controls. The HIV-1 infected patients divided into two groups (HIV/AIDS and non-AIDS) according to their CD4 status. Total IgG antibody titer against MCPV was analyzed by virus like particle (VLP)-based enzyme linked immunosorbent assay (ELISA). Presence of MCPV-DNA in subject's PBMCs was examined by quantitative real-time PCR assay. Levels of anti-MCPV IgG in HIV/AIDS patients were significantly higher than those in non-AIDS HIV-infected and control subjects (p value = <0.001). The prevalence rate of MCPV-DNA in PBMCs of HIV/AIDS, non-AIDS HIV-infected and un-infected controls were 17%, 16%, and 14% respectively. The MCPV viral load among the groups ranged between 0.15 to 2.9 copies/10cells (median, 1.9 copies/10cells), with no significant difference between the studied populations (p value = 0.3).
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http://dx.doi.org/10.1007/s00705-016-3186-zDOI Listing
April 2017

Hp91 immunoadjuvant: An HMGB1-derived peptide for development of therapeutic HPV vaccines.

Biomed Pharmacother 2017 Jan 5;85:148-154. Epub 2016 Dec 5.

Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.

Background: High percentage of human cervical malignancy is related to human papillomavirus (HPV) infections. Thus, it is important to find novel non-invasive treatment strategies among various therapeutic HPV vaccines. In current study, we investigated the protective and therapeutic effects of DNA- and protein-based vaccines using HPV16 E7 as a model antigen in tumor mice model. In this line, the full length of high-mobility group box 1 (HMGB1) protein as well as an HMGB1-derived short peptide (Hp91) was used as an adjuvant for stimulating adaptive immunity and developing the potency of these vaccines.

Methods: DNA vaccination of HPV16 E7 with HMGB1 was performed as the complexed and conjugated forms. The immunostimulatory properties of Hp91 peptide along with Hp121 control peptide were compared to Montanide 720 in protein vaccination.

Results: Our data showed that co-immunization of HPV16 E7 protein with Hp91 peptide or Hp91+Hp121 peptides significantly increased the secretion of IFN-γ, IgG2a antibody response, and protected 100% of mice against a TC-1 tumor challenge. Furthermore, the linkage of HMGB1 with E7 antigen led to enhance the immunogenicity of DNA vaccine especially in combination with Hp91 and Hp121 peptides.

Conclusions: These findings suggest that Hp91 peptide, and the full length of HMGB1 gene could be an efficient adjuvant for improvement of therapeutic HPV protein- and DNA-based vaccines, respectively.
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http://dx.doi.org/10.1016/j.biopha.2016.11.115DOI Listing
January 2017

Smart bomb AS1411 aptamer-functionalized/PAMAM dendrimer nanocarriers for targeted drug delivery in the treatment of gastric cancer.

Clin Exp Pharmacol Physiol 2017 01;44(1):41-51

Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Chemotherapy, a conventional method assessed in recent oncology studies, poses numerous problems in the clinical environment. To overcome the problems inherent in chemotherapy, an intelligent drug delivery system has come to the forefront of cancer therapeutics. In this study, we designed a dendrimer-based pharmaceutical system together with a single-stranded AS1411 aptamer (APT ) as a therapeutic strategy. The polyamidoamine (PAMAM)-polyethylene glycol (PEG) complex was then conjugated with the AS1411 aptamer and confirmed by atomic-force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR) .In this study, we show that the conjugated PAMAM-PEG-APT complex dramatically increased PAMAM-PEG-5-FU uptake by MKN45 gastric cancer cells. We also demonstrated both the stability of the nanoparticle-5-FU-APT complex, by thin layer chromatography (TLC), and an increase in 5-fluorouracil (5-FU) accumulation in the vicinity of cancerous tumors. This smart drug delivery system is capable of effectively transferring 5-FU to MKN45 gastric cancer cells in consistent and without toxic effects.
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http://dx.doi.org/10.1111/1440-1681.12670DOI Listing
January 2017

Prevalence of Merkel Cell Polyomavirus in Tehran: An Age-Specific Serological Study.

Iran Red Crescent Med J 2016 May 14;18(5):e26097. Epub 2016 Feb 14.

Department of Virology, Iran University of Medical Sciences, Tehran, IR Iran.

Background: Several new types of polyomavirus have been discovered in recent years mainly because of the recent state-of-the-art detection technologies. Among the polyomaviruses, Merkel cell polyomavirus (MCPyV) has attracted the most attention because of its possible role in the etiology of Merkel cell carcinoma, a rare but lethal form of skin cancer.

Objectives: This study aimed to determine age-specific seroprevalence of MCPyV in Tehran.

Patients And Methods: In this cross-sectional study, we collected 440 serum samples from healthy individuals 2 to 78 years of age who visited the Pasteur Institute's clinic in Tehran, Iran, using a convenience sampling strategy. We developed a virus-like particle-based enzyme-linked immunosorbent assay that uses VP1, the major capsid protein of MCPyV, to detect and quantitate serum antibodies to MCPyV. We compared the prevalence of MCPyV between males and females and across eight age groups.

Results: A total of 255 (57.9%) of the serum samples were MCPyV positive. The seroprevalence in children under 10 years of age was 25%. The seroprevalence increased to 56% over the next decade of life (10 - 19 years of age). The seroprevalence rate in males and females was 56.1% and 59.7% respectively, and a binary logistic regression showed no significant difference between males and females (P = 0.77). However, the prevalence of MCPyV increased with age (P = 0.012).

Conclusions: Our results suggest that human exposure to MCPyV occurs throughout life. The MCPyV antibody levels remained high among older adults in our population, consistent with reports from other populations.
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http://dx.doi.org/10.5812/ircmj.26097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939235PMC
May 2016

Prime/boost immunization with HIV-1 MPER-V3 fusion construct enhances humoral and cellular immune responses.

Immunol Lett 2015 Dec 27;168(2):366-73. Epub 2015 Oct 27.

Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.

Development of an effective vaccine against HIV-1 infection is a main concern in worldwide. A potent vaccine for HIV-1 requires the induction and maintenance of both humoral and cellular immunity. In this study, the levels of humoral and cellular immune responses were compared using MPER-V3 injection in three immunization strategies such as DNA/DNA, peptide/peptide, and DNA/peptide (prime-boost). MPG peptide and Montanide 720 were used as a DNA delivery system, and as a peptide adjuvant, respectively. Our results demonstrated that MPG forms stable non-covalent nanoparticles with plasmid DNA at N/P ratio of 10:1 (∼ 110-130 nm). The in vitro transfection efficiency of MPER-V3 DNA using MPG was comparable with lipofectamine and turbofect reagents as a common delivery system. In vivo prime-boost immunization using HIV-1 MPER-V3 could significantly enhance humoral and cellular immune responses as compared to control groups. The mixture of IgG1 and IgG2a was observed for each strategy, but IFN-γ production was significantly higher in prime-boost and peptide immunizations than that in DNA immunizations, inducing Th1 response. Moreover, our data showed that prime immunization with low dose of the nanoparticles (MPER-V3 DNA: MPG at ratio of 1:10) followed by MPER-V3 peptide drives T cell responses towards a Th1-type similar to high dose of the naked DNA prime/peptide boost immunization. Generally, the prime-boost strategy could improve both immune responses against MPER and especially V3 peptides suggesting its application as a promising HIV vaccine candidate in future.
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http://dx.doi.org/10.1016/j.imlet.2015.10.012DOI Listing
December 2015

Occult hepatitis B virus infection and S gene escape mutants in HIV-infected patients after hepatitis B virus vaccination.

Int J STD AIDS 2016 10 18;27(11):967-72. Epub 2015 Sep 18.

Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran

Hepatitis B virus (HBV) vaccination is recommended for HIV patients. Despite the relative success of HBV vaccination, breakthrough infections can occur infrequently in patients, and it can be due to occult HBV infection, vaccine unresponsiveness and/or emergence of escape mutants. This study assessed the presence of occult HBV infection and S gene escape mutants in HIV-positive patients after HBV vaccination. Ninety-two HIV-positive patients were enrolled in this study, including 52 responders to HBV vaccine and 40 non-responders. All of the cases received HBV vaccine according to routine HBV vaccination protocols. The presence of HBV-DNA was determined by real-time polymerase chain reaction (PCR). In HBV-DNA positive samples, the most conserved regions of S gene sequences were amplified by nested PCR and PCR products were sequenced. Occult HBV infection was detected in two cases. Glycine to arginine mutation at residue 145 (G145R) within the 'a' region of the S gene was detected in one of the occult HBV infection cases who was in the non-responder group. This study showed that the prevalence of occult HBV infection and vaccine escape mutants was low in our HBV-vaccinated HIV-positive patients in both responder and non-responder groups, so there was no alarming evidence indicating breakthrough HBV infection in our vaccinated HIV-positive cases.
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http://dx.doi.org/10.1177/0956462415602419DOI Listing
October 2016

Development and Characterization of a New Antipeptide Monoclonal Antibody Directed to Human CD20 Antigen.

Cancer Biother Radiopharm 2015 Sep;30(7):310-6

1 National Cell Bank of Iran, Pasteur Institute of Iran . Tehran, Iran .

The rapid expansion of immunotherapeutic approaches for treatment of various diseases, including cancers, has been greatly facilitated by the invention of new generation of antibodies. Clinical studies have indicated that anti-CD20 mAb-based therapies represent an effective treatment for various diseases with overexpression of CD20 on their cell surface, such as non-Hodgkin's lymphoma, hemolytic anemia, as well as autoimmune diseases like rheumatoid arthritis. Technically, due to a short extra membrane domain, the recombinant CD20 protein is a difficult antigen to raise immune responses. In search for new monoclonal antibodies, the authors used an antigenic polypeptide, which yielded numbers of new binders that may lead to production of anti-CD20 antibodies, with improved diagnostic or clinical attributes. Mice were immunized with extra membrane loop of human CD20 (exCD20) polypeptide. The exCD20 antigen showed a desired immune response and was able to develop a monoclonal antibody, 3B4C10, which reacted well with peptide antigen as well as native antigen on the surface of Raji B-cell line. The antibody 3B4C10 with a balanced K(on) and K(off) may be applicable in the construction of affinity columns or beads for isolation and purification of CD20-positive cells and cancer stem cells.
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http://dx.doi.org/10.1089/cbr.2015.1863DOI Listing
September 2015

Frequency and subtype of BK virus infection in Iranian patients infected with HIV.

Med Microbiol Immunol 2016 Feb 4;205(1):57-62. Epub 2015 Jul 4.

Clinical Research Department, Pasteur Institute of Iran, 13164, Pasteur Ave., Tehran, Iran.

Human polyomavirus BK virus (BKV) is a double-stranded DNA virus that infects approximately 90 % of the general population as a subclinical or mild infection. In immunosuppressed patients, such as HIV cases, BKV may be reactivated resulting hemorrhagic cystitis and tubulointerstitial nephritis. However, there are limited studies on prevalence and molecular epidemiology of BKV in Iran. We therefore aimed to evaluate the prevalence and subtypes of BKV in Iranian HIV patients. A total of 99 patients with HIV infection were enrolled in the study. Presence of BKV DNA in plasma was evaluated by nested PCR. PCR products were sequenced directly, and phylogenetic analysis was performed. BKV DNA was detected in 8.08 % of HIV patients. BKV viremia presented in 4 out of 25 patients (16 %) not receiving antiretroviral therapy in comparison with 4 out 74 of HAART-treated patients (5.4 %) (P = 0.023). In patients with CD4 counts ≥200 cells/mm(3), viremia was found more commonly (7/80 = 8.8 %) than in those with lower counts (1/19 = 5.2 %) (not significant). All sequenced BKV isolates belonged to subtype Ib-2. Our findings indicated that the prevalence of BKV viremia is relatively prevalent in patients with HIV infection and significantly higher in naïve than HAART-treated cases. Therefore, HAART can eliminate BKV infection from plasma and reduce viremia although the actual implication of BKV viremia in HIV patients is not clear.
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http://dx.doi.org/10.1007/s00430-015-0426-xDOI Listing
February 2016

Transmitted Drug Resistance Mutations in Antiretroviral-Naïve Injection Drug Users with Chronic HIV-1 Infection in Iran.

PLoS One 2015 11;10(5):e0126955. Epub 2015 May 11.

Department of Pathology and Medical Laboratory Sciences, Faculty of Paramedicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.

The growing incidence and transmission of drug resistant HIV-1 strains due to widespread use of antiretroviral therapy (ART) can jeopardize the success of first-line ART. While there is a known moderate prevalence of transmitted drug resistance (TDR) among newly infected Iranians, no data exist about the rate of these primary resistance mutations among the ART-naïve, chronically infected individuals who are, in fact, the main candidates for ART initiation. To address this issue, we collected blood samples from 40 ART-naïve injection drug-users (IDUs) with chronic HIV-1 infection (seroconversion time ranging from 2 to 9 years) living in Sanandaj, Iran, followed by sequencing of the protease and reverse-transcriptase regions from their HIV-1 genome. Phylogenetic analyses of the sequenced regions revealed that all samples were CRF35_AD. Transmitted resistance mutations were interpreted as surveillance drug-resistant mutations (SDRMs) based on the world health organization (WHO) algorithm. The frequency of SDRMs to any class of antiretroviral drugs was 15%, which included mutations to nucleoside reverse transcriptase inhibitors (NRTIs, 10%), with M41L and M184V as the most common (5%), and non-nucleoside reverse transcriptase inhibitors (NNRTIs, 5%), with K103N as the only detected mutation (5%). Although not in the WHO SDRMs list, several minor protease inhibitor resistant mutations listed in the International Antiviral Society-USA panel were identified, of which M36I, H69K, L89M/V/I (each one 100%) and K20R/T (92.5%) can be considered as polymorphic signatures for CRF35_AD.The relatively high rate of TDR mutations in our study raises concerns about the risk of treatment failure in chronically infected IDUs of Sanandaj city. These results suggest that routine resistance testing should be considered before the therapy initiation in this area. Additional surveillance studies are required to generalize this deduction to other cities of Iran.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126955PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427455PMC
February 2016

No evidence for occult HBV infection in hepatitis B vaccine non-responders.

Iran J Microbiol 2014 Oct;6(5):350-3

Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran.

Background And Objective: Although hepatitis B vaccine immunogenicity is high, certain risk factors such as age, tobacco consumption, obesity and genetic background have been associated with low responsiveness to HBV vaccine. We aimed to evaluate the role of occult hepatitis B virus (HBV) infection in non-responder adults to HBV vaccine in a low endemic area for HBV.

Material And Methods: A total of 52 subjects who were non-responder to HBV vaccine were enrolled in the study. HBsAg, anti-HBs and anti-HBc were tested in all subjects. The presence of HBV-DNA was determined in plasma samples by real-time PCR.

Results: A total of 52 cases with median age 34 years were enrolled in the study. 63.5% of patients were male and 36.5% were female. Isolated anti-HBc (HBsAg negative, anti-HBs negative and anti-HBc positive) was detected in 3.8% of cases. HBV-DNA was not detected in our cases.

Conclusion: This study showed no evidence of occult HBV infection in our HBV vaccine non-responders even in cases with isolated anti-HBc.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385577PMC
October 2014