Ongoing with current combinations of antiretroviral drugs for the treatment of Human Immunodeficiency Virus (HIV) infection can successfully maintain long-term suppression of HIV-1 replication in plasma. Still, none of these therapies is capable of extinguishing the virus from the long-lived cellular reservoir, including monocyte-derived macrophages (MDM), that means the principal obstacle to HIV cure. MDM are widely distributed in all tissues and organs, including central system nervous (CNS) where they represent the most frequent HIV-infected cells that means the principal obstacle to HIV cure. Current FDA-approved antiretroviral drugs target viral reverse transcriptase, protease, integrase, and entry processes (coreceptor or fusion blockade). It is desirable to continue to develop new antiretrovirals directed against alternative targets in the virus lifecycle in order to further optimize therapeutic options, overcome resistance to existing medications, and potentially contribute to the elimination of viral reservoirs.This review provides a comprehensive overview of the activity of antiretroviral drugs (classical and upcoming) in monocytes-derived macrophages (MDM). Defining the antiviral activity of these drugs in this important cellular HIV-1 reservoir provides crucial hints about their efficacy in HIV-1 infected patients.
The scientific interest in the chemical modification of chitosan to increase its solubility and application has led to its conjugation with Schiff bases, which are interesting scaffolds endowed with diverse biological properties. The resultant chitosan-based Schiff bases (CSBs) are widely studied in scientific literature due to the myriad of activities exerted, both catalytic and biological, including anticancer, anti-inflammatory, antioxidant, and especially antimicrobial ones. Antimicrobial resistance (AMR) is one of the major public health challenges of the twenty-first century because it represents a threat to the prevention and treatment of a growing number of bacterial, parasitic, viral, and fungal infections that are no longer treatable with the available drugs. Thus, in this review, we present a brief outline of the biological activities of CSBs as well as their complexes with metals, with a particular focus on the recent literature regarding the antimicrobial effect of these captivating derivatives.
Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3-8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs (p < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.
Abstract Because of the importance of macrophages in the pathogenesis of the disease caused by HIV, we investigated the efficacy of various anti-HIV drugs in human primary macrophages acutely or chronically infected by this virus. The results obtained for acutely infected macrophages show that dideoxynucleosides (AZT, ddI, and ddC), interferon-α and -γ, mismatched double-stranded RNA, Tat inhibitor, phosphorothioate antisense, and inhibitors of HIV protease, all significantly inhibit virus replication at concentrations far below those toxic for the cells. However, in macrophages in which proviral DNA is already integrated (chronically infected macrophages), only the three inhibitors of HIV protease induced significant virus inhibition at concentrations 100 or more times higher than those effective in acutely infected macrophages. Treatment of macrophages with macrophage colony-stimulating factor does not affect the anti-HIV efficacy of protease inhibitors. These results suggest that therapeutic strategies with activity for macrophages, including inhibitors of HIV protease, are worth pursuing in patients with HIV infection. J. Leukoc. Biol. 56: 381–386; 1994.
Transition metal complexes are attracting attention because of their various chemical and biological properties. In particular, the NHC-gold complexes represent a productive field of research in medicinal chemistry, mostly as anticancer tools, displaying a broad range of targets. In addition to the already known biological targets, recently, an important activity in the organization of the cell cytoskeleton was discovered. In this paper, we demonstrated that two NHC-gold complexes (namely AuL4 and AuL7) possessing good anticancer activity and multi-target properties, as stated in our previous studies, play a major role in regulating the actin polymerization, by the means of in silico and in vitro assays. Using immunofluorescence and direct enzymatic assays, we proved that both the complexes inhibited the actin polymerization reaction without promoting the depolymerization of actin filaments. Our outcomes may contribute toward deepening the knowledge of NHC-gold complexes, with the objective of producing more effective and safer drugs for treating cancer diseases.
The novel human immunodeficiency virus type 1-specific thiocarboxanilide derivatives that contain either a substituted furanyl (UC-781) or thienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxyether chain linked to the 4-chlorophenyl ring in meta position show highly favorable antiviral properties. Compounds UC-781 and UC-82 discovered by scientists at Uniroyal Chemical Ltd. proved to be > or = 5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 approximately 0.002 microgram/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, and tetrahydroimidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one. In addition, the compounds were able to knock out virus replication in cell culture at concentrations that were 20-50-fold lower than those of nevirapine or bis(heteroaryl)piperazine. They were also highly efficient (EC50 < or = 0.02 microgram/ml) in suppressing the replication of mutant virus strains that contained mutations in their reverse transcriptase that conferred resistance to other non-nucleoside reverse transcriptase inhibitors (i.e., Tyr181 to Cys, Lys103 to Asn, Val106 to Ala, and Leu100 to Ile). The compounds selected for virus mutants that were only marginally resistant to the thiocarboxanilides ( < 10-20-fold). The antiviral activity of the compounds was only slightly affected by the presence of high concentrations of human serum, and the compounds were shown to be highly stable in the presence of human serum for at least 24 hr at room temperature.
Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico.HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D(N = 228), -A(N = 65) and -E(N = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7–3.8]IU/ml; 3.8[3.5–4.2]IU/ml and 3.9[3.7–4.2]IU/ml, P < 0.001). Results confirmed by multivariable analysis correcting for patients'demographics, HBV-DNA, ALT and infection-status.In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAg<1000IU/ml(P-value from <0.001 to 0.04). These mutations lie in divergent pathways involving other HBsAg C-terminus mutations: V190A + F220L (Phi = 0.41, P = 0.003), S204N + L205P (Phi = 0.36, P = 0.005), Y206F + S210R (Phi = 0.47, P < 0.001) and S210N + F220L (Phi = 0.40, P = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them(P-value from 0.003 to 0.02). In-vitro, the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt(P-value from <0.001 to 0.02). Structurally, these mutational pairs reduced HBsAg C-terminus stability and determined a rearrangement of this domain.In conclusion, HBsAg-levels in genotype-D are significantly lower than in genotype-A and -E in HBeAg-negative patients. In genotype-D, specific mutational clusters in HBsAg C-terminus correlate with lower HBsAg-levels in-vivo, hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression.
In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO.
Macrophages are widely recognized as the second major target of HIV in the body. The cellular characteristics of such resting cells markedly affect the dynamics of virus lifecycle, that is slower but far more prolonged that in lymphocytes. In addition, the limited concentrations of endogenous nucleotide pools in macrophages downregulate the enzymatic activity of reverse transcriptase. As a consequence, both the anti-HIV activity and the development of resistance to antiviral drugs in macrophages are substantially different than those found in activated lymphocytes. These peculiar characteristics of virus replication and efficacy of antiviral drugs in macrophages have a natural in vivo counterpart in extralymphoid tissues, where macrophages account for the majority of cells infected by HIV. Furthermore, the replication of HIV in macrophages of testis and central nervous system is far less affected by antiviral drugs than in lymph nodes, because of the presence of natural barriers that markedly diminish the concentration of such drugs. For all these reasons, HIV infection of macrophages should be taken into account in therapeutic strategies aimed to achieve an optimal therapeutic effect in all tissue compartments where the virus hides and replicates.
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