Search

Aim: To research the synergistic activity of G2-S16 dendrimer and dapivirine (DPV) antiretroviral as microbicide candidate to prevent HIV-1 infection. Materials & methods: We assess the toxicity of DPV on cell lines by MTT assay, the anti-HIV-1 activity of G2-S16 and DPV alone or combined at several fixed ratios. Finally, their ability to inhibit the bacterial growth in vitro was assayed. The analysis of combinatorial effects and the effective concentrations were performed with CalcuSyn software. Conclusion: Our results represent the first proof-of-concept study of G2-S16/DPV combination to develop a safe microbicide.

The development of a safe, effective, and low-priced topical microbicide to prevent HIV-1 sexual transmission is urgently needed. The emerging field of nanotechnology plays an important role in addressing this challenge. We demonstrate that topical vaginal administration of 3% G2-S16 prevents HIV-1JR-CSF transmission in humanized (h)-BLT mice in 84% with no presence of HIV-1 RNA and vaginal lesions. Second-generation polyanionic carbosilane dendrimer G2-S16 with silica core and 16 sulfonate end-groups exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4 interaction, acting on the virus, and inhibiting the cell-to-cell HIV-1 transmission, confirming its multifactorial and non-specific ability. This study represents the first demonstration that transmission of HIV-1 can be efficiently blocked by vaginally applied G2-S16 in h-BLT mice. These findings provide a step forward in the development of G2-S16-based vaginal microbicides to prevent vaginal HIV-1 transmission in humans., From the Clinical Editor: HIV infections remain a significant problem worldwide and the major route of transmission is through sexual activity. In this article, the authors developed an antiviral agent containing polyanionic carbosilane dendrimer with silica core and 16 sulfonate end-groups. When applied vaginally, this was shown to exert anti-HIV protection. These positive findings may offer hope in the fight against the spread of HIV epidemic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Polyanionic carbosilane dendrimers (PCDs) are potential candidates for the development of new microbicides for the prevention of HIV transmission. Tenofovir (TFV), which has dual antiviral activity (anti-HIV/HSV-2), and maraviroc (MRV) are the most studied antiretrovirals as microbicides. Here, we introduce developments in the design of innovative dendrimer-based microbicides. We also review and discuss the combination of various PCDs with TFV and/or MRV for their anti-HIV-1 activity and synergistic combinatory potential. Well-defined combinations blocking HIV-1 infection in early steps of HIV-1 replication provide greater efficacy than monotherapy, as reflected by the decrease in concentration and increase in HIV-1 inhibition. These combinations are characterized by lower doses, which minimize toxic side-effects and the emergence of multi-drug resistant mutants. The above facts suggest that the combination of first- and second-generation PCDs with TFV and/or MRV represents a promising candidate microbicide for preventing HIV-1 sexual transmission and simultaneously suppressing HSV-2., From the Clinical Editor: HIV infection remains a significant and unresolved problem for humankind, despite the development of combination antiretroviral therapy. It has been found that polyanionic carbosilane dendrimers have efficacy in preventing HIV transmission. In this comprehensive review article, the authors discuss the current status and latest development of the use of dendrimers in combination with other antiretroviral drugs as microbicides, which should stimulate others into further research in the fight against HIV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The development of novel strategies to prevent HIV-1 infection is of outstanding relevance. Metal complexes of Cu(2+), Ni(2+), Co(2+) and Zn(2+) derived from sulfonated and carboxylated poly(propylene imine) dendrimers with ethylenediamine core were evaluated as tunable antiviral agents against HIV-1. After demonstrating their biocompatibility, specific trends in the antiviral properties were found, related to both the dendritic scaffold (peripheral group, generation) and the bound metal ions (sort, amount). In HEC-1A and VK-2 cell lines, as model of the first barrier against HIV-1 infection, a high preventive inhibitory action was found, which also avoided virus internalization inside cells and inhibited both CCR5 and CXCR4 HIV-1 strains. In peripheral blood mononuclear cells (PBMC), as model of the second barrier, a dual preventive and therapeutic behavior was observed. A rational design of such metallodendrimers opens new avenues for the production of versatile and efficient treatments against HIV-1 infection., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objectives: The safety, immunogenicity, impact on the latent reservoir and rebound of viral load after therapeutic HIV-1 vaccination with recombinant modified vaccinia Ankara-based (MVA-B) HIV-1 vaccine expressing monomeric gp120 and the fused Gag-Pol-Nef polyprotein of clade B with or without a drug to reactivate latent HIV-1 (disulfiram) were assessed., Methods: HIV-1-infected patients were randomized to receive three injections of MVA-B (n = 20) or placebo (n = 10). Twelve patients (eight who received vaccine and four who were given placebo) received a fourth dose of MVA-B followed by 3 months of disulfiram. Combined ART (cART) was discontinued 8 weeks after the last dose of MVA-B. Clinical Trials.gov identifier: NCT01571466., Results: MVA-B was safe and well tolerated. A minor, but significant, increase in the T cell responses targeting vaccine inserts of Gag was observed [a median of 290, 403 and 435 spot-forming-cells/10(6) PBMCs at baseline, after two vaccinations and after three vaccinations, respectively; P = 0.02 and P = 0.04]. After interruption of cART, a modest delay in the rebound of the plasma viral load in participants receiving vaccine but not disulfiram was observed compared with placebo recipients (P = 0.01). The dynamics of the viral load rebound did not change in patients receiving MVA-B/disulfiram. No changes in the proviral reservoir were observed after disulfiram treatment., Conclusions: MVA-B vaccination was a safe strategy to increase Gag-specific T cell responses in chronically HIV-1-infected individuals, but it did not have a major impact on the latent reservoir or the rebound of plasma viral load after interruption of cART when given alone or in combination with disulfiram., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aim: To research the synergistic activity by triple combinations of carbosilane dendrimers with tenofovir and maraviroc as topical microbicide., Methods: Cytotoxicity, anti-HIV-1 activity, vaginal irritation and histological analysis of triple combinations were determined. Analysis of combined effects and the median effective concentration were performed using CalcuSyn software., Results: Combinations showed a greater broad-spectrum anti-HIV-1 activity than the single-drug, and preserved this activity in acid environment or seminal fluid. The strongest combinations were G2-STE16/G2-S24P/tenofovir, G2-STE16/G2-S16/maraviroc and G2-STE16/tenofovir/maraviroc at 2:2:1, 10:10:1 10:5:1 ratios, respectively. They demonstrated strong synergistic activity profile due to the weighted average combination indices varied between 0.06 and 0.38. No irritation was detected in female BALB/c mice., Conclusion: The three-drug combination increases their antiviral potency and act synergistically as potential microbicide.

Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide., From the Clinical Editor: This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides., (© 2014.)

Background: To evaluate the possible effect of zidovudine (ZDV) on inmunoglobins production in infants born to HIV-1 infected women., Subjects and Methods: We have studied the immunoglobulins serum levels in 57 non-infected children born to HIV-infected mothers. The children were divided into two groups: group A, 28 children born to HIV-1 infected mothers that received ZDV on protocol 076 conditions, and group B, 29 children born to mothers that did not receive anti-HIV-1 drugs. Quantification of serum IgG, IgA and IgM was performed by nephelometric techniques., Results: The median time to reach normal IgA values at 12 months, was 25.57 months (confidence interval [CI] 95%: 22.01-29.12) in the children of group A and 12.67 months (CI 95%: 9.90-15.44) in the children of group B (p = 0.01). The median time to reach normal IgM values at 12 months was 15.93 months (CI 95%: 15.21-16.65) in group A children versus 11.20 months (CI 95%: 8.51-13.89) in group B (p = 0.11). The median time to reach normal IgG values at 12 months was 19.67 months (CI 95%: 13.12-16.22) in group A children versus 12.73 months (CI 95%: 11.16-14.30) in group B (p = 0.05). The normal IgA levels were reached 2.36 (CI 95%: 1.16-4.81) times later in group A than in group B children (p = 0.02), whereas normal IgG levels were reached 1.88 (CI 95%: 0.94-3.78) times later in group A than in group B of children., Conclusions: Our results indicate that treatment of pregnant mothers with ZDV clearly affect the ability of their newborns to produce inmunoglobulins, which may have important practical implications for their vaccination protocols.