RESUMO
BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) has been associated with leukemia/lymphoma (ATL) and myelopathy/tropical spastic paraparesis (HAM/TSP), in addition to other inflammatory diseases as well as infection complications. Therapeutic approaches for HTLV-1-related pathologies are limited. The labdane diterpene myriadenolide (AMY) is a natural product that exhibit biological activities, such as anti-inflammatory and antiviral activity as reported for HIV and herpesvirus. RESULTS: We demonstrated that this natural product was able to inhibit the expression of gag-pol mRNA and substantially reduced the expression of the structural proteins p19 and gp46. Comparison of treated and untreated cells shows that AMY alters both the morphology and the release of viral particles. The Atomic Force Microscopy assay showed that the AMY treatment reduced the number of particles on the cell surface by 47%. CONCLUSION: We demonstrated that the labdane diterpene myriadenolide reduced the expression of the structural proteins and the budding of viral particles, besides induces altered morphogenesis of HTLV-1, conferring on AMY a new antiviral activity that may be useful for the development of new compounds with specific anti-HTLV-1 activity.
Assuntos
Antivirais/farmacologia , Diterpenos/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Morfogênese/efeitos dos fármacos , RNA Mensageiro/genética , Anti-Inflamatórios/farmacologia , Fatores Biológicos/farmacologia , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Humanos , Células JurkatRESUMO
The ophthalmic presentation of relapse in a patient with human T-lymphotropic virus type 1 (HTLV1) associated adult T-cell lymphoma leukaemia is described. Epidemiology, clinical features and therapeutic options are briefly reviewed. Antenatal screening and inclusion of HTLV1 in the differential diagnosis of inflammatory and neuromuscular eye conditions should be considered in endemic regions.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/efeitos da radiação , Trinidad e TobagoRESUMO
There is no effective therapy for human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Glucocorticoids are effective to reduce the motor disability in these patients, but its role as anti-spastic drugs is unknown. Here it is reported the use of corticosteroids in HAM/TSP. The goal was to find reliable molecular markers linked to treatment effectiveness. The clinical efficacy of corticosteroids was studied in 22 HAM/TSP. The treatment was a single dose of 7.0 mg of systemic betamethasone. Pre-treatment samples were obtained immediately before steroid administration and post-treatment samples were collected after 5 days. Neurological disability was evaluated by the Osame's Motor Disability Scales. Relative levels of Tax, Foxp3, IL-10, TGF-ß, CTLA-4, and GITR mRNA were measured and the percentage of CD4(+) Foxp3(+) and CD4(+) Tax(+) populations was quantified in PBMCs by real-time PCR and flow cytometry, respectively. The same parameters were studied in eight untreated carriers. Betamethasone treatment showed neurological improvement in 21 HAM/TSP patients, with one patient without response to treatment. This therapy was associated with a decrease in Tax mRNA load and CD4(+) Tax(+) T cells in HAM/TSP. Simultaneously, an increase in Foxp3 mRNA and CD4(+) Foxp3(+) T cell was detected in these patients. The other markers studied had no significant changes after treatment. Clinical improvement in betamethasone-treated HAM/TSP was associated with an inverse relationship between a decrease in Tax and an increase in Foxp3 at the mRNA and protein levels. These results suggest that both Tax and Foxp3 may represent potential biomarkers for drug treatment assessments in HAM/TSP.
Assuntos
Betametasona/uso terapêutico , Fatores de Transcrição Forkhead/sangue , Produtos do Gene tax/sangue , Vírus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical/tratamento farmacológico , Adulto , Idoso , Antígenos CD/sangue , Betametasona/administração & dosagem , Biomarcadores/sangue , Linfócitos T CD4-Positivos/virologia , Citocinas/sangue , Feminino , Citometria de Fluxo , Produtos do Gene tax/genética , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Leucócitos Mononucleares , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/virologia , Reação em Cadeia da Polimerase , RNA Mensageiro , Carga ViralRESUMO
This study investigated the anti-viral effects of the polyphenolic compounds Quercetin and Kaempherol on the release of HTLV-1 from the surface of MT-2 cells. Atomic force microscopy (AFM) was used to scan the surface of the MT-2 cells. MT-2 cells were fixed with 100% methanol on round glass lamina or cleaved mica and dried under UV light and laminar flow. The images were captured on a Multimode equipment monitored by a NanoScope IIId controller from Veeco Instruments Inc operated in tapping mode and equipped with phase-imaging hardware. The images demonstrated viral budding structures 131 ± 57 nm in size, indicating profuse viral budding. Interestingly, cell-free viruses and budding structures visualized on the surface of cells were less common when MT-2 was incubated with Quercetin, and no particles were seen on the surface of cells incubated with Kaempherol. In summary, these data indicate that HTLV-1 is budding constantly from the MT-2 cell surface and that polyphenolic compounds were able to reduce this viral release. Biological samples were analyzed with crude cell preparations just after cultivation in the presence of Quercetin and Kaempherol, showing that the AFM technique is a rapid and powerful tool for analysis of antiviral activity of new biological compounds.
Assuntos
Antivirais/farmacologia , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Quempferóis/farmacologia , Quercetina/farmacologia , Linfócitos T/ultraestrutura , Linfócitos T/virologia , Liberação de Vírus/efeitos dos fármacos , Microscopia de Força AtômicaRESUMO
Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is chronic progressive myelopathy characterized by bilateral pyramidal tracts involvement with sphincteric disturbances. HTLV-I infects approximately 10-20 million people worldwide. There are large endemic areas in southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa. Since the primary neuropathological feature of HAM/TSP is chronic inflammation caused by HTLV-I infection in the spinal cord, various treatments focusing on immunomodulatory or anti-viral effects were performed for HAM/TSP patients until now. However, there are still many of problems, such as insufficient effects, side effects and expensive costs in long-term treatments, etc., in these treatments. Therefore, an ideal therapeutic strategy against HAM/TSP is still not established yet. Although only a small proportion of HTLV-I-infected individuals develops HAM/TSP, neurological symptoms are certainly progressive once myelopathy develops, leading to deterioration of the quality of life. Therefore, we now need the therapeutic regimens to protect the development, or be able to commence the treatments as soon as possible after the development safely and inexpensively even in long-term course or lifelong course of treatment. As HTLV-I-infected CD4(+) T cells are the first responders in the immunopathogenesis of HAM/TSP, the ideal treatment is the elimination of HTLV-I-infected cells from the peripheral blood. In this article, we will review the therapeutic strategies against HAM/TSP up to now and will introduce our new therapeutic approach focusing on the targeting of HTLV-I-infected cells in HAM/TSP patients.
Assuntos
DNA Viral/análise , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Interferon gama/uso terapêutico , Paraparesia Espástica Tropical/tratamento farmacológico , África , Líquido da Lavagem Broncoalveolar , Região do Caribe , Portador Sadio/tratamento farmacológico , Portador Sadio/virologia , Contagem de Células , Linhagem Celular , Diagnóstico Diferencial , Infecções por HTLV-I/complicações , Infecções por HTLV-I/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Humanos , Japão , Leucócitos Mononucleares/virologia , Oriente Médio , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/virologia , América do Sul , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/virologia , Doenças da Medula Espinal/tratamento farmacológico , Células Th1/virologiaRESUMO
This work evaluated the effect of a sulphated fucan extracted from the Laminaria abyssalis marine algae on the human T cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation. The experiments were carried out in HeLa cells cocultured with a HTLV-1-infected T cell line (C91/PL cells) in the presence of the sulphated polysaccharide at concentration below that corresponding to the ED50. The sulphated fucan inhibited almost 100% of the syncytium formation at concentration of 100 microg/mI and was still active (>95%) at a concentration of 25 microg/ml. It was also observed that the best inhibition occurred when the compound was added in the first 2 h of the cell-to-cell contact. This is the first report showing that a purified sulphated polysaccharide, extracted from marine algae, is able to inhibit the cell-to-cell contact essential for the spreading of the HTLV-1.
Assuntos
Células Gigantes/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Laminaria/química , Polissacarídeos/farmacologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Sulfato de Dextrana/farmacologia , Células Gigantes/virologia , Infecções por HTLV-I/virologia , Células HeLa , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Linfócitos T/virologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
Extracts from four species of Brazilian marine algae collected from the Rio de Janeiro State coast were screened to determine the inhibitory effect on HTLV-1-induced syncytium formation. Before performing the syncytium inhibition assay the 50% cytotoxic dose (CyD50) of the algal extracts was evaluated. The antiviral test was carried out in HeLa cells co-cultured with HTLV-I infected T-cell line (C91/PL cells) in the presence of marine algal extracts in the concentration inferior to that corresponding to the CyD50. It was observed that co-cultured cells exposed to Ulva fasciata extract showed 60.2% syncytium inhibition at a concentration of 2.5%. At 5% concentration, Sargassum vulgare and Vidalia obtusiloba extracts presented 78.8 and 76% syncytium inhibition, respectively. The best inhibitory activity was observed with Laminaria abyssalis that presented 100% syncytium inhibition at a concentration of 2.5%. This work shows that extracts of marine algae, mainly L. abyssalis extract, are able to inhibit the cell-to-cell contact essential for the spreading of the virus and could be useful to prevent the infection.
Assuntos
Proteínas de Algas/farmacologia , Eucariotos/química , Células Gigantes/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Brasil , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Efeito Citopatogênico Viral , Sulfato de Dextrana/farmacologia , Células Gigantes/virologia , Células HeLa/citologia , Células HeLa/efeitos dos fármacos , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Células K562/citologia , Células K562/efeitos dos fármacos , Replicação ViralRESUMO
When present for a first time blood donation, a 28-year-old Brazilian white female reported a pruritic eczema of the scalp and retroauricular areas since childhood that had been frequently infected. Her mother had been diagnosed as having HTLV-I-associated myelopathy (HAM), and the patient was found to be a human T-lymphotropic virus type-I (HTLV-I) carrier. The patient had been breast-fed for 6 months. The patient had a complete examination, and a biopsy was taken from eczema in the retroauricular area. The byopsy indicated chronic lymphohistiocytic dermatitis with no abnormal lymphocystes. Eleven months later, the patient had an infliltration in the skin of the retroauricular area and a new biopsy revealed atypical lymphocytes. Nested polymerase chain reaction (PCR) was positive for HTLV-I and immunohistochemistry of the tissue at this time confirmed adult T-cell leukemia/lymphoma (ATLL). Retrospective immunohistochemistry showed that the first fragment submitted from the biopsy 11 months before was also compatible with the diagnosis of ATLL. This case fulfilled all major criteria for diagnosis of HTLV-I-associated infective dermatitis (HTLV-I-ID). We postulate that the patient has indolent ATLL associated with HTLV-I infective dermatitis since childhood. We recommended that tissue immunohistochemistry analysis be done in any patient with HTLV-associated infective dermatitis.