RESUMEN
The aging process of long-term self-renewing hematopoietic stem/progenitor cells is not yet completely understood and recent studies on antiapoptotic cell pathways have demonstrated a close linkage between telomerase activation and Bcl-2 deregulation in human cancer cells. The present work shows that human T cell leukemia virus type II (HTLV-II) Mo virions that have originated from the T cell line (C344), but not from the B cell line (BJAB), are critically involved in mediating survival and growth effects on hematopoietic precursors (represented by both the TF-1 CD34+ cell line and by peripheral blood-derived CD34+ cells) through the maintenance or enhancement of telomerase activity and the induction of bcl-2 expression. In addition, using an interleukin-3-dependent TF-1 cell line, it was demonstrated that IL-3 deprivation was sufficient to influence the levels of telomerase activity and Bcl-2 expression in CD34+ cells. Taken together, these findings suggest that, in appropriate conditions, extended hematopoietic progenitor cell survival and proliferation following HTLV-II exposure depends on a synergistic interaction between up-regulation of Bcl-2 and activation of telomerase activity.
Asunto(s)
Antígenos CD34/análisis , Células Madre Hematopoyéticas/enzimología , Células Madre Hematopoyéticas/inmunología , Virus Linfotrópico T Tipo 2 Humano/fisiología , Telomerasa/metabolismo , Linfocitos B/enzimología , Linfocitos B/virología , Regulación de la Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/virología , Humanos , Interleucina-3/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Linfocitos T/enzimología , Linfocitos T/virología , Telomerasa/efectos de los fármacos , Células Tumorales Cultivadas/virología , Virión/fisiologíaRESUMEN
The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF-alpha were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta were also determined in IL-2-stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8(+) T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4(+) T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1alpha. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines. (Blood. 2000;95:2760-2769)
Asunto(s)
Infecciones por VIH/complicaciones , VIH-1/fisiología , Infecciones por HTLV-II/complicaciones , Linfocitos/inmunología , Linfocitos/virología , Proteínas Inflamatorias de Macrófagos/sangre , Replicación Viral , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Células Cultivadas , Quimiocina CCL3 , Quimiocina CCL4 , Citocinas/sangre , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Infecciones por HTLV-II/inmunología , Infecciones por HTLV-II/virología , Humanos , Interleucina-2/farmacología , Linfocitos/efectos de los fármacos , Proteínas Inflamatorias de Macrófagos/biosíntesis , Proteínas Inflamatorias de Macrófagos/farmacología , Masculino , Provirus/aislamiento & purificación , Análisis de Regresión , Carga Viral , Replicación Viral/efectos de los fármacosRESUMEN
Reaction of the title ligands (HPyTSC and HS(S)PPh2, respectively) with R2SnO (R = Me, Et, Bu) in ethanol (EtOH) afforded the complexes [SnMe2(PyTSC) (S2PPh2)].EtOH (1) and [SnR2(PyTSC) (S2PPh2)] (R = Et (2), Bu (3)). The structures of 1 and 2 were determined by single-crystal X-ray diffractometry. In both these complexes the tin atom is coordinated to an N,N,S-dentate thiosemicarbazonate ligand, an anisobidentate dithiophosphinato ligand and the two R groups. The coordination polyhedrons can be described as distorted pentagonal bipyramids. A comparative study of the IR spectra of 1, 2 and 3 indicates that the butyl complex has a similar structure. Multinuclear (1H, 13C, 31P and 119Sn) NMR data suggest that the structures of 1 and 2 probably remain in CDCl3 (or DMSO-d6) solution but compound 3 partially decomposes in these media. Preliminary results on the effects of the complexes on the proliferation and differentiation of FLC, CEM, U937, K562 and TOM-1 leukaemia cells, and on the clonogenic activity of K562 cells are also described.