RESUMEN
The human T-cell leukemia virus type 1 (HTLV-1) was first described in 1980. It is spread in highly endemic regions in the world, such as the Southwestern part of Japan, sub-Saharan Africa and South America, Caribbean, Middle East, and Australo-Melanesia regions. HTLV-1 causes adult T cell leukemia and is associated with many inflammatory conditions, most notably HTLV-1-associated myelopathy/tropic spastic paraparesis. HTLV-2, first isolated in 1982, was recognized as a common infection in intravenous drug users, but a clear association with disease remains elusive. The first estimate of HTLV-1-positive individuals worldwide, in 1993, was around 10-20 millions. Due to the lack of global population-based prevalence studies, this is considered an underestimate at the moment. Furthermore, HTLV-1 prevalence in Europe is impacted by changing migration flows. Particularly, no data on HTLV-1 prevalence in the general population in Italy are available. Here, we report a systematic literature review of studies conducted in Italy on HTLV-1/2 from 1980 to 2023. Based on the criteria we adopted a total of 426 publications were found (64 reviews, 99 epidemiological, and 263 translational studies). The contents of some representative publications are summarized and discussed. Moreover, an approximate estimation of about 26,000 HTLV-1 positive foreigners living in Italy was obtained from updated data of foreigners from each single country officially registered as resident in Italy and from data on HTLV-1 prevalence among the general population in the corresponding countries.
Asunto(s)
Infecciones por HTLV-I , Infecciones por HTLV-II , Virus Linfotrópico T Tipo 1 Humano , Humanos , Infecciones por HTLV-I/epidemiología , Infecciones por HTLV-II/epidemiología , Italia/epidemiología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Prevalencia , Virus Linfotrópico T Tipo 2 HumanoRESUMEN
Iminosugars' similarity to carbohydrates determines the exceptional potential for this class of polyhydroxylated alkaloids to serve as potential drug candidates for a wide variety of diseases such as diabetes, lysosomal storage diseases, cancer, bacterial and viral infections. The presence of lipophilic substituents has a significant impact on their biological activities. This work reports the synthesis of three new pyrrolidine lipophilic derivatives O-alkylated in C-6 position. The biological activities of our iminosugars' collection were tested in two cancer cell lines and, due to the pharmaceutical potential, in the model yeast system Saccharomyces cerevisiae to assess their toxicity.
Asunto(s)
Iminoazúcares , Iminoazúcares/farmacología , Inhibidores EnzimáticosRESUMEN
Isoxazoline-carbocyclic monophosphate nucleotides were designed and synthesized through the chemistry of nitrosocarbonyl intermediates and stable anthracenenitrile oxide. Docking and molecular dynamics studies were first conducted for determining the best candidate for polymerase SARS-CoV-2 inhibition. The setup phosphorylation protocol afforded the nucleotides available for the biological tests. Preliminary inhibition and cytotoxicity assays were then performed, and the results showed a moderate activity of the nucleotides accompanied by cytotoxicity.
RESUMEN
The human T-cell leukemia virus type 1 (HTLV-1) is the only known human oncogenic retrovirus. HTLV-1 can cause a type of cancer called adult T-cell leukemia/lymphoma (ATL). The virus is transmitted through the body fluids of infected individuals, primarily breast milk, blood, and semen. At least 5-10 million people in the world are infected with HTLV-1. In addition to ATL, HTLV-1 infection can also cause HTLV-I-associated myelopathy (HAM/TSP). ATL is characterized by a low viral expression and poor prognosis. The oncogenic mechanism triggered by HTLV-1 is extremely complex and the molecular pathways are not fully understood. However, viral regulatory proteins Tax and HTLV-1 bZIP factor (HBZ) have been shown to play key roles in the transformation of HTLV-1-infected T cells. Moreover, several studies have shown that the final fate of HTLV-1-infected transformed Tcell clones is the result of a complex interplay of HTLV-1 oncogenic protein expression with cellular transcription factors that subvert the cell cycle and disrupt regulated cell death, thereby exerting their transforming effects. This review provides updated information on the mechanisms underlying the transforming action of HTLV-1 and highlights potential therapeutic targets to combat ATL.
Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Femenino , Humanos , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Proteínas de los Retroviridae/genética , Proteínas de los Retroviridae/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Carcinogénesis , Transformación Celular Neoplásica/genéticaRESUMEN
Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Compuestos Orgánicos de Estaño , Compuestos de Trialquiltina , Cisplatino , Línea Celular Tumoral , Compuestos de Trialquiltina/farmacología , Antineoplásicos/farmacología , Compuestos Orgánicos de Estaño/farmacologíaRESUMEN
Regulated cell death (RCD) plays an important role in the progression of viral replication and particle release in cells infected by herpes simplex virus-1 (HSV-1). However, the kind of RCD (apoptosis, necroptosis, others) and the resulting cytopathic effect of HSV-1 depends on the cell type and the species. In this study, we further investigated the molecular mechanisms of apoptosis induced by HSV-1. Although a role of caspase-8 has previously been suggested, we now clearly show that caspase-8 is required for HSV-1-induced apoptosis in a FADD-/death receptor-independent manner in both mouse embryo fibroblasts (MEF) and human monocytes (U937). While wild-type (wt) MEFs and U937 cells exhibited increased caspase-8 and caspase-3 activation and apoptosis after HSV-1 infection, respective caspase-8-deficient (caspase-8-/-) cells were largely impeded in any of these effects. Unexpectedly, caspase-8-/- MEF and U937 cells also showed less virus particle release associated with increased autophagy as evidenced by higher Beclin-1 and lower p62/SQSTM1 levels and increased LC3-I to LC3-II conversion. Confocal and electron microscopy revealed that HSV-1 stimulated a strong perinuclear multivesicular body response, resembling increased autophagy in caspase-8-/- cells, entrapping virions in cellular endosomes. Pharmacological inhibition of autophagy by wortmannin restored the ability of caspase-8-/- cells to release viral particles in similar amounts as in wt cells. Altogether our results support a non-canonical role of caspase-8 in both HSV-1-induced apoptosis and viral particle release through autophagic regulation.
Asunto(s)
Herpesvirus Humano 1 , Animales , Ratones , Humanos , Herpesvirus Humano 1/metabolismo , Caspasa 8/metabolismo , Apoptosis , Autofagia , Virión/metabolismo , Caspasa 3/metabolismoRESUMEN
Based on previous experience in our laboratory, we developed a real-time reverse transcriptase (RT) quantitative PCR (RT-qPCR) assay for the assessment of very low levels of HIV-1 RT activity. The RNA, acting as a template for reverse transcription into cDNA by HIV-1 RT, consisted of a synthetic RNA ad hoc generated by in vitro transcription and included a coding sequence for HSV-1 gD (gD-RNA-synt). Different conditions of variables involved in the RT-qPCR reaction, notably different amounts of gD-RNA-synt, different mixes of the reaction buffer, and different dNTP concentrations, were tested to optimize the assay. The results indicated that the gD-RNA-synt-based RT assay, in its optimized formulation, could detect a specific cDNA reverse transcription even in the presence of 1 × 10-9 U of HIV RT. This achievement greatly improved the sensitivity of the assay over previous versions. In summary, this constructed RT-qPCR assay may be considered a promising tool for providing accurate information on very low HIV-1 RT activity.
RESUMEN
Testing HIV-1 RNA in plasma by PCR is universally accepted as the ultimate standard to confirm diagnosis of HIV-1 infection and to monitor viral load in patients under treatment. However, in some cases, this assay could either underestimate or overestimate the replication capacity of a circulating or latent virus. In the present study, we performed the assessment of evaluating the HIV-1 reverse transcriptase (RT) activity by means of a new assay for the functional screening of the status of HIV-1 patients. To this purpose, we utilized, for the first time on blood samples, an adapted version of a real-time RT quantitative PCR assay, utilized to evaluate the HIV-1-RT inhibitory activity of compounds. The study analyzed blood samples from 28 HIV-1-infected patients, exhibiting a wide range of viremia and immunological values. Results demonstrated that plasma HIV-1 RT levels, expressed as cycle threshold values obtained with the assay under appraisal, were inversely and highly significantly correlated with the plasma HIV-1-RNA levels of the patients. Thus, an HIV-1 RT quantitative PCR assay was created which we describe in this study, and it may be considered as a promising basis for an additional tool capable of furnishing information on the functional virological status of HIV-1-infected patients.
RESUMEN
Two new families of N,O-nucleoside analogues containing the anthracene moiety introduced through the nitrosocarbonyl ene reaction with allylic alcohols were prepared. The core structure is an isoxazolidine heterocycle that introduces either atom either a phenyl ring or dimethyl moiety at the C3 carbon. Different heterobases were inserted at the position 5 of the heterocyclic ring. One of the synthesized compounds demonstrated a good capacity to induce cell death and an appreciable nuclear fragmentation was evidenced in treated cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Nucleósidos/síntesis química , Nucleósidos/metabolismo , Antracenos/química , Humanos , Modelos Moleculares , Estructura Molecular , Oxazoles/química , Propanoles/química , Relación Estructura-Actividad , Células U937RESUMEN
The human T cell leukemic/lymphotropic virus type 1 (HTLV-1), discovered several years ago, is the causative agent for a rapid progressive haematological malignancy, adult T cell leukemia (ATL), for debilitating neurological diseases and for a number of inflammatory based diseases. Although the heterogeneous features of the diseases caused by HTLV-1, a common topic concerning related therapeutic treatments relies on the use of antiretrovirals. This review will compare the different approaches and opinions in this matter, giving a concise overview of preclinical as well as clinical studies covering all the aspects of antiretrovirals in HTLV-1 infection. Studies will be grouped on the basis of the class of antiretroviral, putting together both pre-clinical and clinical results and generally following a chronological order. Analysis of the existing literature highlights that a number of preclinical studies clearly demonstrate that different classes of antiretrovirals, already utilized as anti-HIV agents, are actually capable to efficiently contrast HTLV-1 infection. Nevertheless, the results of most of the clinical studies are generally discouraging on the same point. In conclusion, the design of new antiretrovirals more specifically focused on HTLV-1 targets, and/or the establishment of early treatments with antiretrovirals could hopefully change the perspectives of diseases caused by HTLV-1.
RESUMEN
Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFNα and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless IκBα phosphorylation is inhibited. Since the constitutive activation of NF-kappa B (NF-κB) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of IκBα phosphorylation seems a potential strategy for treating and preventing HTLV-1 related pathologies. In this study, we have demonstrated that a combination treatment with the IκBα phosphorylation inhibitor Bay 11-7085 and AZT induced increased levels of regulated cell death (RCD) by apoptosis compared to the single treatments in HTLV-1 infected cells of different origin. Importantly, levels of RCD were considerably higher in infected cells in comparison with the uninfected ones. Inhibition of NF-κB activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-κB complex proteins, p65/p52. Moreover, a transcriptional analysis revealed that the addition of Bay 11-7085 to AZT treatment in HTLV-1-infected cells modified their transcriptional profile, by inducing the upregulation of some pro-apoptotic genes together with the downregulation of some anti-apoptotic genes. Our data suggest that addition of adequate concentrations of IκBα phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.
RESUMEN
Herpes simplex virus 1 (HSV-1) can infect a wide range of cell types, including cells of the adaptive and innate immunity but, normally, it completes a fully-permissive replication cycle only in epithelial or neural cells. Complex mechanisms controlling this delicate balance in immune cells and consequent restriction of HSV-1 infection in these cells have not been completely elucidated. We have recently demonstrated that the transcription factor nuclear factor kappa B (NF-κB) can act as a main permissiveness regulator of HSV-1 infection in monocytic cells, however, mediators involved in this regulation have not been identified. To better define mechanisms involved in this phenomenon and, particularly, the possible involvement of ROS, wild type U937 cells or U937 cells stably transfected with a dominant-negative (DN) IκB-mutant and selenium-containing compounds, as anti-oxidants, were utilized. The main results can be summarized as follows. HSV-1 infection induces an immediate ROS production in U937 monocytic cells that can efficiently activate NF-κB but not in DN-IκB-mutant cells. Treatment with selenium-containing antioxidants efficiently inhibited HSV-1-induced ROS generation while producing increased levels of HSV-1 replication and a reduction of HSV-1-induced NF-κB activation in U937 monocytic cells. Our results suggest a scenario in which an efficient NF-κB-dependent ROS production in response to infection could contribute in limiting HSV-1 replication in monocytes/macrophages, thus avoiding possible irreparable damage to the innate immune system of the host during HSV-1 infection.
Asunto(s)
Herpes Simple/metabolismo , Herpesvirus Humano 1/fisiología , Monocitos/metabolismo , FN-kappa B/metabolismo , Herpes Simple/genética , Herpes Simple/virología , Herpesvirus Humano 1/genética , Humanos , FN-kappa B/genética , Especies Reactivas de Oxígeno/metabolismo , Células U937 , Replicación ViralRESUMEN
The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a-c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.
Asunto(s)
Diseño de Fármacos , Pirimidinas/química , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Técnicas de Química Sintética , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirimidinas/síntesis química , Relación Estructura-Actividad Cuantitativa , Inhibidores de la Transcriptasa Inversa/síntesis químicaRESUMEN
The biology of HIV is rather complex due to high rate of replication, frequent recombination, and introduction of mutations. This gives rise to a number of distinct variants referred as quasispecies. In addition, the latency within reservoir allows the periodic reactivation of virus replication. The rapid replication of HIV allows immune response escape and establishment of resistance to therapy that can be acquired through drug selection and/or transmitted among individuals. This prompted, over the years, the development of a range of assays aimed to determine drug resistance and sensitivity, to be used both in clinical practice and in antiviral research. Reverse transcriptase (RT) inhibitors have an eminent place among the anti-HIV drugs, being constantly present from the beginning until today in the most commonly used antiviral regimens. This mini-review seeks to provide an up-to-date overview of recent efforts in developing even more reliable and simple methods, of both genotypic and phenotypic types, for specifically detecting drug resistance and sensitivity to RT inhibitors.
Asunto(s)
Pruebas Diagnósticas de Rutina , Farmacorresistencia Viral Múltiple , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacología , Técnicas de Genotipaje , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Humanos , Replicación ViralRESUMEN
Nitrosocarbonyl mesitylene intermediate undergoes an ene reaction with cinnamyl alcohol affording the corresponding 5-hydroxy-isoxazolidine in fair yields. The synthesized 5-acetoxy-isoxazolidine serves as synthon for the preparation of 6-chloropurine N,O-nucleoside analogues, according to the Vorbrüggen reaction. The compounds were evaluated for their metabolic and apoptotic activity, and their structure-activity relationship is discussed.
RESUMEN
Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma (ATL), HTLV-1 associated myelopathy (HAM/TSP), and of a number of inflammatory diseases with an estimated 10-20 million infected individuals worldwide. Despite a number of therapeutic approaches, a cure for ATL is still in its infancy. Conventional chemotherapy has short-term efficacy, particularly in the acute subtype. Allogeneic stem cell transplantation offers long-term disease control to around one third of transplanted patients, but few can reach to transplant. This prompted, over the past recent years, the conduction of a number of clinical trials using novel treatments. Meanwhile, new data have been accumulated on biological and molecular bases of HTLV-1 transforming and infecting activity. These data offer new rational for targeted therapies of ATL. Taking into account the double-face of ATL as an hematologic malignancy as well as a viral infectious disease, this Mini-Review seeks to provide an up-to-date overview of recent efforts in the understanding of the mechanisms involved in already used therapeutic regimens showing promising results, and in selecting novel drug targets for ATL.
RESUMEN
Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a ß-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site. Overall, 10 compounds were prepared and some of that submitted to molecular modelling studies (to investigate their interactions with the active site of IN), to metal titration studies (to detect their chelating capability) and to biological assays.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , Modelos Moleculares , Dominio Catalítico , Quelantes/química , Integrasa de VIH/química , Inhibidores de Integrasa VIH/química , Humanos , Metales/química , Polifenoles/química , Relación Estructura-ActividadRESUMEN
Assessing the actual efficacy of compounds to directly inhibit HIV reverse transcriptase (RT) activity is a main goal in preclinical antiretroviral studies. Our previous studies demonstrated that the effects of inhibitor compounds towards HIV-RT could be efficiently assessed through a simple cell-free assay based on conventional reverse transcription PCR. In the present study, we describe a modified variant of our assay, termed RT real-time quantitative PCR inhibitory assay (RT-qPCR-IA), in which the ability of compounds to restrict the complementary DNA (cDNA) generation by HIV-RT using a specific RNA template is performed by the real-time technique, in order to improve both accuracy and sensitivity of the method. As specific RNA template, RNA extracted from stable transfectants ectopically expressing the herpes simplex virus 1 glycoprotein D gene was utilized. HIV-RT, of both commercial or house-made viral lysate origin, was employed for the assay. To assess the reliability of RT-qPCR-IA, we performed a comparative, quantitative analysis of the dose-dependent effect exerted by known nucleotide and non-nucleotide reverse-transcriptase inhibitors, using the SYBR Green dye chemistry as detection system. The results obtained with RT-qPCR-IA were compared to that obtained using a one-step PicoGreen technology-based commercial kit. The outcome of our study indicates that the development of the novel RT-qPCR-IA will provide rapid and accurate evaluation of the inhibitory efficacy of compounds towards HIV-RT activity. This evaluation could be very useful for large-scale screening of potential new anti-HIV drugs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Inhibidores de la Transcriptasa Inversa/farmacología , ADN Complementario , VIH/enzimología , VIH/genética , Transcriptasa Inversa del VIH/genética , Humanos , ARN Viral/genética , Reproducibilidad de los Resultados , Transcripción Reversa/efectos de los fármacos , Sensibilidad y EspecificidadRESUMEN
In spite of the consistent benefits for HIV-1 infected patients undergoing antiretroviral therapy, a complete immune reconstitution is usually not achieved. Actually, antiretroviral therapy may be frequently accompanied by immunological unresponsiveness, persistent inflammatory conditions and inefficient cytotoxic T-cell response. Thymosin alpha 1 is a thymic peptide that demonstrates a peculiar ability to restore immune system homeostasis in different physiological and pathological conditions (i.e., infections, cancer, immunodeficiency, vaccination and aging) acting as multitasking protein depending on the host state of inflammation or immune dysfunction. This review reports the present knowledge on the in vitro and in vivo studies concerning the use of thymosin alpha 1 in HIV-1 infection. Recent findings and future perspectives of therapeutic intervention are discussed.
Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Timosina/análogos & derivados , Terapia Antirretroviral Altamente Activa , Humanos , Linfocitos/citología , Linfocitos/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Timalfasina , Timosina/farmacologíaRESUMEN
Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.