scholarly journals Preclinical Evaluation of Synthetic −2 RANTES as a Candidate Vaginal Microbicide To Target CCR5

2006 ◽  
Vol 50 (4) ◽  
pp. 1497-1509 ◽  
Author(s):  
Tina M. Kish-Catalone ◽  
Wuyuan Lu ◽  
Robert C. Gallo ◽  
Anthony L. DeVico
Keyword(s):  
Sexual Transmission ◽  
Zealand White Rabbit ◽  
Host Cells ◽  
Sexually Transmitted ◽  
Vaginal Microbicide ◽  
Aids Epidemic ◽  
Swiss Webster Mouse ◽  
Potential Strategy ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT A potential strategy that can be used to combat the worldwide AIDS epidemic is the development of a vaginal microbicide that prevents the sexual transmission of human immunodeficiency virus type 1 (HIV-1). Certain CC chemokines, including RANTES, MIP-1α, and MIP-1β, might facilitate the development of such microbicides since they potently suppress HIV-1 infection by binding to CCR5, the viral coreceptor used by most sexually transmitted strains of HIV-1 to enter host cells. In this study, we evaluated whether a CCR5-specific fragment of RANTES that lacks two N-terminal residues (−2 RANTES) and possesses especially potent HIV-1 suppressive activity has toxicity profiles conducive to the advancement of testing in candidate microbicide formulations. Analyses were carried out with a synthetic version of the chemokine, which was formulated with either Novasomes 7474, a nonphospholipid liposome, or methylcellulose gel. Dialysis studies demonstrated that the formulated −2 RANTES was released from both vehicles and retained anti-HIV-1 activity. Preclinical toxicity studies carried out with Swiss Webster mouse and New Zealand White rabbit vaginal irritation models demonstrated minimal inflammation and minimal adverse changes in cervicovaginal tissue integrity after short-term (10 min) and long-term (24 h) exposure to formulations containing up to 1 mg/ml of −2 RANTES. Similarly, no toxicity was observed with formulations of bioactive murine RANTES in the Swiss Webster mouse vaginal irritation model. Overall, these preclinical studies suggest that −2 RANTES is suitable for further testing as a candidate anti-HIV-1 microbicide.

scholarly journals Settings for identifying recent HIV infections: the Portuguese experience

2008 ◽  
Vol 13 (36) ◽  
Author(s):  
H Cortes Martins ◽  
M T Paixão
Keyword(s):  
Hiv Infections ◽  
Cross Sectional Study ◽  
Western European Country ◽  
Reference Laboratory ◽  
Cross Sectional ◽  
Sexually Transmitted ◽  
Aids Epidemic ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Portugal has been the western European country with the highest rate of notified acquired immunodeficiency syndrome (AIDS) cases since 1999 and human immunodeficiency virus (HIV) infection cases since 2000. Nonetheless, exact information on the magnitude and trends of recently acquired infections is missing. In a cross-sectional study we aimed to determine HIV prevalence, the proportion of recently acquired infections and the incidence among patients attending a Sexually Transmitted Infections (STI) clinic and among HIV positive cases tested at the AIDS Reference Laboratory (ARL), by using the Avidity Index (AI) of antibodies to identify recent HIV-1 seroconversions. Demographic and behavioural data were collected. At the STI clinic 253 patients were enrolled, 16 were found to be HIV infected (14 HIV-1, 2 HIV-2) and a prevalence of 6.3% was obtained. Four recent HIV-1 infections were identified and the HIV-1 incidence was 3.3% per year. At the ARL, 332 newly diagnosed cases of HIV-1 infection were studied, 59 (17.8%) were recent infections and an annual incidence of 4.1% was estimated. These findings support STI clinics as key sentinel sites for recently acquired HIV infections and illustrate the viability of testing for recent HIV infections in these settings and reinforce the value of this method in the surveillance for better monitoring current trends of the HIV/AIDS epidemic in Portugal.

scholarly journals Engineering of Lactobacillus jensenii To Secrete RANTES and a CCR5 Antagonist Analogue as Live HIV-1 Blockers

2010 ◽  
Vol 54 (7) ◽  
pp. 2994-3001 ◽  
Author(s):  
Luca Vangelista ◽  
Massimiliano Secchi ◽  
Xiaowen Liu ◽  
Angela Bachi ◽  
Letong Jia ◽  
...  
Keyword(s):  
T Cells ◽  
Sexual Transmission ◽  
Ccr5 Antagonist ◽  
Strong Activity ◽  
Promising Strategy ◽  
Lactobacillus Jensenii ◽  
Proinflammatory Activity ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Prevention Of Hiv

ABSTRACT The development of effective microbicides for the prevention of HIV-1 sexual transmission represents a primary goal for the control of AIDS epidemics worldwide. A promising strategy is the use of bacteria belonging to the vaginal microbiota as live microbicides for the topical production of HIV-1 inhibitors. We have engineered a human vaginal isolate of Lactobacillus jensenii to secrete the anti-HIV-1 chemokine RANTES, as well as C1C5 RANTES, a mutated analogue that acts as a CCR5 antagonist and therefore is devoid of proinflammatory activity. Full-length wild-type RANTES and C1C5 RANTES secreted by L. jensenii were purified to homogeneity and shown to adopt a correctly folded conformation. Both RANTES variants were shown to inhibit HIV-1 infection in CD4+ T cells and macrophages, displaying strong activity against HIV-1 isolates of different genetic subtypes. This work provides proof of principle for the use of L. jensenii-produced C1C5 RANTES to block HIV-1 infection of CD4+ T cells and macrophages, setting the basis for the development of a live anti-HIV-1 microbicide targeting CCR5 in an antagonistic manner.

Lymphokine-Activated Killer (LAK) Cell Anti-HIV-1 ADCC Reactivity: A Potential Strategy for Reduction of Virus-Infected Cellular Reservoirs

1998 ◽  
Vol 79 (2) ◽  
pp. 115-120 ◽  
Author(s):  
Douglas S Tyler ◽  
S.David Stanley ◽  
John A Bartlett ◽  
Dani P Bolognesi ◽  
Kent J Weinhold
Keyword(s):  
Lak Cell ◽  
Potential Strategy ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals 1,1,3-Trioxo-2H,4H-Thieno[3,4-e][1,2,4]Thiadiazine (TTD) Derivatives: a New Class of Nonnucleoside Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitors with Anti-HIV-1 Activity

1998 ◽  
Vol 42 (3) ◽  
pp. 618-623 ◽  
Author(s):  
M. Witvrouw ◽  
M. E. Arranz ◽  
C. Pannecouque ◽  
R. Declercq ◽  
H. Jonckheere ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Host Cells ◽  
Cross Resistance ◽  
Reverse Transcriptase Inhibitors ◽  
Relationship Analysis ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 μM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3′-azido-3′-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.

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 Impact of HIV‐1 viremia or sexually transmitted infection on semen‐derived anti‐HIV‐1 antibodies and the immunosuppressive capacity of seminal plasma

2019 ◽  
Vol 49 (12) ◽  
pp. 2255-2258
Author(s):  
Kevin J. Selva ◽  
Benjamin R. Bavinton ◽  
Andrew E. Grulich ◽  
Marzena Pazgier ◽  
Anthony D. Kelleher ◽  
...  
Keyword(s):  
Seminal Plasma ◽  
Sexually Transmitted Infection ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
Anti Hiv ◽  
Hiv 1

3-Hydroxyphthaloyl-β-Lactoglobulin. I. Optimization of Production and Comparison with other Compounds Considered for Chemoprophylaxis of Mucosally Transmitted Human Immunodeficiency Virus Type 1

1997 ◽  
Vol 8 (2) ◽  
pp. 131-139 ◽  
Author(s):  
AR Neurath ◽  
AK Debnath ◽  
N Strick ◽  
Y-Y Li ◽  
K Lin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Chemical Modification ◽  
Elevated Temperatures ◽  
Sexual Transmission ◽  
Immunodeficiency Virus ◽  
Sexual Transmission Of Hiv ◽  
Β Lactoglobulin ◽  
Anti Hiv ◽  
Hiv 1

Modification of the major bovine whey protein, β-lactoglobulin (β-LG) by 3-hydroxyphthalic anhydride (3HP) leads to the generation of a potent inhibitor of infection by human immunodeficiency virus (HIV) types 1 and 2, designated 3HP-β-LG. 3HP-β-LG also has antiviral activity against herpesviruses, albeit at concentrations exceeding those required for inhibition of HIV-1 infection. The topical application of 3HP-β-LG to decrease the rate of sexual transmission of HIV and other sexually transmitted viruses worldwide is being considered. Results presented here: (i) define the conditions for chemical modification of β-LG by 3HP, resulting in 3HP-β-LG with optimum anti-HIV-1 activity; (ii) show that β-LG, prior to chemical modification, or 3HP-β-LG can be exposed to the elevated temperatures used to pasteurize milk without adversely affecting anti-HIV-1 activity; (iii) provide evidence that 3HP-β-LG is a more potent anti-HIV-1 compound than sulphated polysaccharides, other candidate compounds considered as prophylactic agents to prevent sexual transmission of HIV-1; and (iv) confirm that the primary target for 3HP-β-LG is CD4, although binding to the HIV-1 envelope protein gp120 was also observed and contributed to the antiviral activity of 3HP-β-LG.

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.

Structure Based Drug Design: Clinically Relevant HIV-1 Integrase Inhibitors

2019 ◽  
Vol 18 (31) ◽  
pp. 2664-2680 ◽  
Author(s):  
Maninder Kaur ◽  
Ravindra K. Rawal ◽  
Goutam Rath ◽  
Amit K. Goyal
Keyword(s):  
Structural Features ◽  
Review Article ◽  
Host Cells ◽  
Integrase Inhibitors ◽  
Structure Based Drug Design ◽  
Hiv Resistance ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Structural Insights ◽  
Hiv 1

HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyzes the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In the last two decades, a number of integrase inhibitors have been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents. This review article summarizes the structural insights required for the inhibition of the HIV1 integrase in the context of clinically relevant HIV1 integrase inhibitors. Additionally, the structural features required for overcoming HIV resistance have been discussed. These insights will update the ongoing design of novel antiviral inhibitors.

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