Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for ...addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH-gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.
The development of a safe and effective microbicide to prevent the sexual transmission of human immunodeficiency virus (HIV)-1 is urgently needed. Unfortunately, the majority of microbicides, such as ...poly(L-lysine)-dendrimers, anionic polymers, or antiretrovirals, have proved inactive or even increased the risk of HIV infection in clinical trials, most probably due to the fact that these compounds failed to prevent semen-exposed HIV infection. We showed that G2-S16 dendrimer exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4/CCR5 interaction and providing a barrier to infection for long periods, confirming its multifactorial and nonspecific ability. Previously, we demonstrated that topical administration of G2-S16 prevents HIV transmission in humanized BLT mice without irritation or vaginal lesions. Here, we demonstrated that G2-S16 is active against mock- and semen-exposed HIV-1 and could be a promising microbicide against HIV infection.
Anionic carbosilane dendrons decorated with sulfonate functions and one thiol moiety at the focal point have been used to synthesize water‐soluble gold nanoparticles (AuNPs) through the direct ...reaction of dendrons, gold precursor, and reducing agent in water, and also through a place‐exchange reaction. These nanoparticles have been characterized by NMR spectroscopy, TEM, thermogravimetric analysis, X‐ray photoelectron spectroscopy (XPS), UV/Vis spectroscopy, elemental analysis, and zeta‐potential measurements. The interacting ability of the anionic sulfonate functions was investigated by EPR spectroscopy with copper(II) as a probe. Different structures and conformations of the AuNPs modulate the availability of sulfonate and thiol groups for complexation by copper(II). Toxicity assays of AuNPs showed that those produced through direct reaction were less toxic than those obtained by ligand exchange. Inhibition of HIV‐1 infection was higher in the case of dendronized AuNPs than in dendrons.
Capturing gold: Water‐soluble gold nanoparticles (AuNPs) have been isolated with pendant anionic sulfonate carbosilane dendrons. The antiviral properties of dendronized AuNPs are higher than that of the free dendrons (see figure).
Amyloid fibrils, which are present in semen, were considered to be a cause of topical vaginal gel ineffectiveness in vivo after microbicides failed as HIV-1 prophylaxis. Therefore, it was necessary ...to determine whether a dendrimer was suitable for further evaluation in an in vitro model of semen-enhanced viral infection (SEVI). We demonstrated that SEVI in TZM.bl cell cultures increased the infectivity of R5-HIV-1NL(AD8), pTHRO.c and pCH058.c isolates, causing higher IC50 values for two polyanionic carbosilane dendrimers, G2-STE16 and G3-S16. However, both dendrimers maintained protection rates of 90% at non-toxic concentrations. When dendrimers were combined with Tenofovir/Maraviroc (TDF/MVC), the anti-HIV-1 effect remained at a minimum IC50 increase between 1- and 7-fold in the presence of amyloid fibrils. In peripheral blood mononuclear cells (PBMC), IC50 values were slightly influenced by the presence of semen. In brief, dendrimers combined with antiretrovirals showed a synergistic effect. This result plays a crucial role in new microbicide formulations, as it overcomes the negative effects of amyloid fibrils.
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Unprotected heterosexual intercourse is the first route for sustaining the global spread of human immunodeficiency virus type 1 (HIV-1), being responsible for 80% of new HIV-1 infections in the ...world. The presence of inflammation in the female reproductive tract and the presence of semen increases the risk of heterosexual HIV-1 transmission. This state-of-the-art research based on an innovative nanotechnology design was focused on a toxicological study of the limitation of the activity of the novel H
2
O-soluble anionic carbosilane dendrimer G2-S16 in the adult cervical and foreskin epithelia. The G2-S16 dendrimer did not cause any irritation or inflammation in the vaginal epithelium, proving that this dendrimer is a safe nanocompound for vaginal application to control viral transmission. It was shown that no significant differences were found in mortality, sublethal or teratogenic effects when the zebra fish embryos were treated with G2-S16. In short, G2-S16 seems to be an ideal candidate for the development of a topical microbicide against HIV-1 infection and the next step is try in clinical trials, because of its great
in vivo
biocompatibility, as well as its ability to halt HIV-1 infection in the presence of semen.
Unprotected heterosexual intercourse is the first route for sustaining the global spread of human immunodeficiency virus type 1 (HIV-1), being responsible for 80% of new HIV-1 infections in the world.
Microbicides are an important strategy for preventing the sexual transmission of HIV but, so far, the most advanced tenofovir-based microbicides have had modest efficacy. This has been related to ...adherence problems and high prevalence of tenofovir-resistant HIV-1 strains. P3 is a new peptide with potent activity against HIV that may be a good microbicide candidate. In this work P3 was formulated in a gel of hydroxyethyl cellulose and its activity, stability and safety profile in Balb/c mice were evaluated. HIV infection was fully blocked by a 1.5% gel containing P3 at the IC90 (366.4 nM) concentration. The antiviral activity did not change at 4°C during 4 months and at 25, 37 and 65°C for 1 week. P3 was stable and fully functional at acidic pH up to 24h, under different concentrations of hydrogen peroxide and in the presence of genital fluids up to 48h. P3 had no antibacterial activity and did not affect sperm motility and vitality. Finally, P3 didn't cause significant alterations in the vaginal epithelium of Balb/c mice at 0.06 (456.8 μM) and 0.2 mg/day (1522.7 μM) doses. These findings indicate that P3 is an excellent candidate for further development as a microbicide gel for the prevention of HIV transmission in women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Versatile synthetic approach designed for anionic bow-tie carbosilane dendrimers.•Comparative biomedical study attending to the topology of carbosilane dendrimers.•Dendron or bow-tie ...interact with the biological receptors more efficiently.•Topology plays an important role for tuning biological or biomedical applications.
A simple and versatile synthetic approach was designed for the formation of sulfonate-terminated bow-tie carbosilane dendrimers with different cores as hydroquinone moiety, triazol ring or carbamate group. These systems were designed to compare biological and biomedical properties attending to the shape or topology of the carbosilane dendritic systems: spherical, dendrons and bow-tie architectures. Biocompatibility and HIV antiviral activity were measured in TZM.bl cells as human epithelial cell line. Sulfonate groups at the periphery of the dendritic systems were selected due to the ability of previously reported anionic dendrimers to interact with important receptor in viral infection. Finally, experimental results were compared with theoretical data showing a clear relationship between topology and biological activity, being a parameter to consider for exploring biomedical applications.
Background
The IL7RA polymorphisms have recently been associated with CD4+ T‐cell decline in untreated HIV‐infected subjects and CD4+ T‐cell recovery in patients on combination antiretroviral therapy ...(cART). The aim of this study was to evaluate whether IL7RA polymorphisms are associated with CD4+ T‐cell recovery in HIV‐infected patients on long‐term cART.
Study design
We performed a retrospective study in 151 naïve cART patients with severe immunodeficiency (CD4+ counts ≤200 cells/mm3). IL7RA polymorphisms' genotyping was performed using Sequenom's MassARRAY platform. The outcome variable was the time to achieve the first value of CD4+ count ≥500 cells/mm3 during the follow‐up.
Results
Two different trends of CD4+ T‐cell recovery were found in Kaplan–Meier analysis. During the first 48 months, 60 of 151 (39·7%) of the patients reached CD4+ T‐cell values ≥500 cells/mm3, and no differences were observed between IL7RA genotypes. After the first 48 months of follow‐up, 27 of 151 (17·8%) of the patients reached CD4+ T‐cell values ≥500 cells/mm3, with a different pattern of CD4+ recovery depending on IL7RA genotype. Patients with rs10491434 TT genotype and rs6897932 TT genotype were more likely of achieving CD4+ value ≥500 cells/mm3 than patients with rs10491434 CT/CC genotype (adjusted hazard ratio (aHR) = 3·59; P = 0·005) and patients with rs6897932 CC/CT genotype (aHR = 11·7; P < 0·001).
Conclusions
The IL7RA polymorphisms seem to be associated with CD4+ T‐cell recovery in HIV‐infected patients who started cART with severe immunodeficiency, in the second phase of CD4+ T‐cell recovery after long‐term cART.
Abstract
Immune mechanisms that modulate human immunodeficiency virus-1 (HIV-1) reservoir size in neonates are poorly understood. Using samples from neonates who initiated antiretroviral therapy ...shortly after birth, we demonstrate that interleukin-8–secreting CD4 T cells, which are selectively expanded in early infancy, are more resistant to HIV-1 infection and inversely correlated with the frequency of intact proviruses at birth. Moreover, newborns with HIV-1 infection displayed a distinct B-cell profile at birth, with reduction of memory B cells and expansion of plasmablasts and transitional B cells; however, B-cell immune perturbations were unrelated to HIV-1 reservoir size and normalized after initiation of antiretroviral therapy.
Clinical Trials Registration. NCT02369406.
IL-8–secreting CD4 T cells are inversely correlated with HIV-1 reservoir size at birth in vertically infected neonates; these CD4 T cells may therefore represent a barrier against HIV-1 reservoir seeding.
Background
The adiponectin (ADIPOQ) rs2241766 polymorphism is related to metabolic abnormalities. The aim of this study was to evaluate the association of the ADIPOQ rs2241766 polymorphism with serum ...dyslipidemia and insulin resistance (IR) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)‐coinfected patients.
Methods
We carried out a cross‐sectional study on 262 patients. ADIPOQ rs2241766 polymorphisms were genotyped by GoldenGate® assay. Generalized linear models (GLMs) were used to compare continuous outcome variables (total cholesterol (TC), triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C and homeostatic model assessment (HOMA)) and categorical outcome variables (TC ≥ 200 mg/dL, TG ≥ 170 mg/dL, LDL‐C ≥ 100 mg/dL, HDL‐C ≤ 35 mg/dL, non‐HDL‐C ≥ 120 mg/dL and HOMA ≥ 3·8) according to ADIPOQ genotype under a dominant inheritance model.
Results
Patients with the rs2241766 GG/GT genotype had significantly lower serum TC levels (P = 0·038) and percentages of TC ≥ 200 mg/dL (P = 0·022) than rs2241766 TT carriers. When adjusted GLM was performed, rs2241766 GG/GT was associated with low serum TC levels (arithmetic mean ratio (AMR) = 0·92 (95% CI = 0·85; 0·99) P = 0·024) and low likelihood of TC ≥ 200 mg/dL (odds ratio (OR) = 0·32 (95% CI = 0·11; 0·88) P = 0·027. When stratifying by steatosis, no significant values were found for patients without steatosis. However, for patients with steatosis, rs2241766 GG/GT genotypes were related to low TC serum values of TC (AMR = 0·89; P = 0·027), LDL‐C (AMR = 0·85; P = 0·039) and non‐HDL‐C (AMR = 0·86; P = 0·015). No significant associations were found between rs2241766 and HOMA values.
Conclusions
The presence of the ADIPOQ rs2241766 G allele (GG/GT genotype) was associated with a protective effect against dyslipidemia, primarily in HIV/HCV‐coinfected patients with steatosis.
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