A novel chemical approach integrating the benefits of nanoparticles with versatility of coordination chemistry is reported herein to increase the effectiveness of well-known HIV antiretroviral drugs. ...The novelty of our approach is illustrated using a catechol ligand tethered to the known antiretroviral azidothymidine (AZT) as a constitutive building block of the nanoparticles. The resulting nanoscale coordination polymers (NCPs) ensure good encapsulation yields and equivalent antiretroviral activity while significantly diminishing its cytotoxicity. Moreover, this novel family of nanoparticles also offers (i) long-lasting drug release that is dissimilar inside and outside the cells depending on pH, (ii) triggered release in the presence of esterases, activating the antiviral activity in an on-off manner due to a proper chemical design of the ligand and (iii) improved colloidal stabilities and cellular uptakes (up to 50-fold increase). The presence of iron nodes also adds multifunctionality as possible contrast agents. The present study demonstrates the suitability of NCPs bearing pharmacologically active ligands as an alternative to conventional antiretroviral treatments.
Iron-based nanoscale coordination polymers as novel drug delivery systems for efficient HIV/AIDS therapy.
Objectives
A relationship between obesity and intestinal bacterial translocation has been reported. Very little information is available with respect to the involvement of the bacterial translocation ...mechanistic pathway in HIV-1/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). We determined whether lipopolysaccharide (LPS)-binding protein (LBP), cluster of differentiation 14 (CD14), myeloid differentiation protein 2 (MD2) and toll-like receptor 4 (TLR4) single-nucleotide polymorphisms and LPS, LBP and soluble CD14 (sCD14) plasma levels are involved in HALS.
Patients and methods
This cross-sectional multicentre study involved 558 treated HIV-1-infected patients, 240 with overt HALS and 318 without HALS. Anthropometric, clinical, immunovirological and metabolic variables were determined. Polymorphisms were assessed by genotyping. Plasma levels were determined by ELISA in 163 patients (81 with HALS and 82 without HALS) whose stored plasma samples were available. Student's t-test, one-way ANOVA, two-way repeated measures ANOVA, the χ
2 test and Pearson and Spearman correlation analyses were carried out for statistical analysis.
Results
LBP rs2232582 T→C polymorphism was significantly associated with HALS (P = 0.01 and P = 0.048 for genotype and allele analyses, respectively). Plasma levels of LPS (P = 0.009) and LBP (P < 0.001) were significantly higher and sCD14 significantly lower (P < 0.001) in patients with HALS compared with subjects without HALS. LPS levels were independently predicted by triglycerides (P < 0.001) and hepatitis C virus (P = 0.038), LBP levels by HALS (P < 0.001) and sCD14 levels by age (P = 0.008), current HIV-1 viral load (P = 0.001) and protease inhibitor use (P = 0.018).
Conclusions
HALS is associated with LBP polymorphism and with higher bacterial translocation.
BACKGROUNDHIV-1 infected individuals have an increased cardiovascular risk which is partially mediated by dyslipidemia. Single nucleotide polymorphisms in multiple genes involved in lipid transport ...and metabolism are presumed to modulate the risk of dyslipidemia in response to antiretroviral therapy.
METHODSThe contribution to dyslipidemia of 20 selected single nucleotide polymorphisms of 13 genes reported in the literature to be associated with plasma lipid levels (ABCA1, ADRB2, APOA5, APOC3, APOE, CETP, LIPC, LIPG, LPL, MDR1, MTP, SCARB1, and TNF) was assessed by longitudinally modeling more than 4400 plasma lipid determinations in 438 antiretroviral therapy-treated participants during a median period of 4.8 years. An exploratory genetic score was tested that takes into account the cumulative contribution of multiple gene variants to plasma lipids.
RESULTSVariants of ABCA1, APOA5, APOC3, APOE, and CETP contributed to plasma triglyceride levels, particularly in the setting of ritonavir-containing antiretroviral therapy. Variants of APOA5 and CETP contributed to high-density lipoprotein-cholesterol levels. Variants of CETP and LIPG contributed to non-high-density lipoprotein-cholesterol levels, a finding not reported previously. Sustained hypertriglyceridemia and low high-density lipoprotein-cholesterol during the study period was significantly associated with the genetic score.
CONCLUSIONSSingle nucleotide polymorphisms of ABCA1, APOA5, APOC3, APOE, and CETP contribute to plasma triglyceride and high-density lipoprotein-cholesterol levels during antiretroviral therapy exposure. Genetic profiling may contribute to the identification of patients at risk for antiretroviral therapy-related dyslipidemia.
Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus ...load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy.
We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed.
In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004).
Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.
Introduction:
Antiretroviral drugs have been associated with several toxicities that limit their success. Of the chronic toxicities, the lipodystrophy syndrome is of special concern due to the ...metabolic alterations that can accompany it. Why some patients treated with a particular antiretroviral regimen develop lipodystrophy, while others do not, is a medical mystery, but it has been suggested that individuals may (or may not) have a genetically conditioned predisposition. Pharmacogenetics is the science that studies how the genetic composition of individuals can give rise to interindividual variations in response to drugs and drug toxicity.
Areas covered:
This article reviews the published investigations on the association between host genetic determinants in treated HIV-infected patients and the presence of lipodystrophy. Studies were identified through a PubMed database search. Case-control and longitudinal studies into pharmacogenetic association were selected. Areas covered include the data on the genetic variants of mitochondrial parameters, cytokines, adipokines, proteins involved in adipocyte biology and proteins involved in stavudine metabolism.
Expert opinion:
Most studies provide inconsistent data due to partial genetic evaluation, different assessment of lipodystrophy and low number of patients evaluated. The pharmacogenetics of lipodystrophy in HIV-infected patients treated with antiretroviral drugs still belongs in the research laboratory.
Background and Objectives Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis ...(TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. Methods This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and X2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. Results Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81 plus or minus 0.2 vs. 2.94 plus or minus 0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). Conclusions HALS is associated with decreased sTWEAK levels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract A decrease in HIV-1 specific CD8 T-cell responses associated with a partial control of viral replication occurred in 12 HIV-1-infected patients during autologous dendritic cells vaccination. ...HIV CD8 T cells were detected in 6/10 patients during immunizations, increasing after HAART discontinuation in 3 of them. Tet+ CD8 cells mainly had an effector phenotype (CD45RA−/+ CCR7− and CD28− and Perf+/−) and maintained IFN-γ release throughout follow-up. By contrast, patients with CD45RA−/+ CCR7+ Perf+ HIV-specific cells showed a decrease in peptide-specific IFN-γ production during vaccinations while levels were recovered when off HAART. No major mutations in either Gag p24 and p17 immunodominant epitopes were observed that might have explained the impaired CD8+ T-cell responses. Taken together, heterogeneity in the maturation status of HIV-specific CD8 T cells may be partially involved in the drop of peptide-specific IFN-γ production during immunizations.
General population studies have shown associations between copy number variation (CNV) of the LPA gene Kringle-IV type-2 (KIV-2) coding region, single-nucleotide polymorphism (SNP) rs6415084 in LPA ...and coronary heart disease (CHD). Because risk factors for HIV-infected patients may differ from the general population, we aimed to assess whether these potential associations also occur in HIV-infected patients.
A unicenter, retrospective, case-control (1:3) study. Eighteen HIV-patients with confirmed diagnosis of acute myocardial infarction (AMI) were adjusted for age, gender, and time since HIV diagnosis to 54 HIV-patients without CHD. After gDNA extraction from frozen blood, both CNV and SNP genotyping were performed using real-time quantitative PCR. All genetic and non-genetic variables for AMI were assessed in a logistic regression analysis.
Our results did not confirm any association in terms of lipoprotein(a) LPA structural genetic variants when comparing KIV-2 CNV (p = 0.67) and SNP genotypes (p = 0.44) between AMI cases and controls. However, traditional risk factors such as diabetes mellitus, hypertension, and CD4(+) T cell count showed association (p < 0.05) with CHD.
Although significant associations of AMI with diabetes, hypertension and CD4(+) T cell count in HIV-patients were found, this study could not confirm the feasibility neither of KIV-2 CNV nor rs6415084 in LPA as genetic markers of CHD in HIV-infected patients.
● Individuals with HIV infection are at higher risk of coronary heart disease (CHD) than the non-infected population.● Our results showed no evidence of LPA structural genetic variants associated with CHD in HIV-1-infected patients.● Associations were found between diabetes mellitus, arterial hypertension, CD4(+) T cell count, and CHD.● The clinical usefulness of these biomarkers to predict CHD in HIV-1-infected population remains unproven.● Further studies are needed to assess the contribution of common genetic variations to CHD in HIV-infected individuals.
The potential for mitochondrial (mt) DNA mutation accumulation during antiretroviral therapy (ART), and preferential accumulation in patients with lipoatrophy compared with control participants, ...remains controversial. We sequenced the entire mitochondrial genome, both before ART and after ART exposure, in 29 human immunodeficiency virus (HIV)—infected Swiss HIV Cohort Study participants initiating a first-line thymidine analogue—containing ART regimen. No accumulation of mtDNA mutations or deletions was detected in 13 participants who developed lipoatrophy or in 16 control participants after significant and comparable ART exposure (median duration, 3.3 and 3.7 years, respectively). In HIV-infected persons, the development of lipoatrophy is unlikely to be associated with accumulation of mtDNA mutations detectable in peripheral blood.
The main goal of this study was to assess the role of mycophenolate mofetil (MMF) during interruption of highly active antiretroviral therapy (HAART). Seventeen patients with early-stage chronic HIV ...type 1 infection were treated with HAART for 12 months. They were then randomized (day 0) to receive MMF (HAART-MMF group, n = 9) or to continue the regimen (HAART group, n = 6) for 120 additional days. At day 120 in the HAART-MMF group, HAART was discontinued, and MMF administration was continued. The primary end point of the study was the number of individuals maintaining a plasma viral load (VL) set point of <200 copies/mL after at least 6 months off HAART. At day 120, all patients in both groups had undetectable plasma VLs. After 6 months off HAART, 5 of 9 patients in the HAART-MMF group versus 1 of 6 patients in the HAART group maintained a plasma VL of <200 copies/mL (P = 0.28). According to the ability of their plasma to inhibit cellular proliferation, patients were reclassified and divided into an inhibition group (n = 6) and a no inhibition group (n = 9). The doubling time of VL rebound was significantly higher in the inhibition group (mean +/- SE, 10.22 +/- 1.3) than in the no inhibition group (mean +/- SE, 4.6 +/- 1.6; P = 0.03). Moreover, 5 of 6 patients in the inhibition group maintained a plasma VL of <200 copies/mL versus 1 of 9 patients in the no inhibition group (P = 0.005) after 6 months off HAART. We found that combining MMF and HAART delayed VL rebound and improved control of viral replication without HAART but only when inhibition of lymphocyte proliferation was achieved.
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