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1.
Stem Cells ; 39(10): 1410-1422, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34028139

RESUMO

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Using a highly efficient protocol for direct reprogramming of adult human fibroblasts with chemically modified mRNA, we report the first generation of HD induced neural precursor cells (iNPs) expressing striatal lineage markers that differentiated into DARPP32+ neurons from individuals with adult-onset HD (41-57 CAG). While no transcriptional differences between normal and HD reprogrammed neurons were detected by NanoString nCounter analysis, a subpopulation of HD reprogrammed neurons contained ubiquitinated polyglutamine aggregates. Importantly, reprogrammed HD neurons exhibited impaired neuronal maturation, displaying altered neurite morphology and more depolarized resting membrane potentials. Reduced BDNF protein expression in reprogrammed HD neurons correlated with increased CAG repeat lengths and earlier symptom onset. This model represents a platform for investigating impaired neuronal maturation and screening for neuronal maturation modifiers to treat HD.


Assuntos
Doença de Huntington , Células-Tronco Neurais , Corpo Estriado , Humanos , Doença de Huntington/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/metabolismo
2.
J Virol ; 88(4): 2327-32, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24284326

RESUMO

The antiviral lectins griffithsin (GRFT), cyanovirin-N (CV-N), and scytovirin (SVN), which inhibit several enveloped viruses, including lentiviruses, were examined for their ability to inhibit entry mediated by Env proteins of delta- and gammaretroviruses. The glycoproteins from human T-cell leukemia virus type 1 (HTLV-1) were resistant to the antiviral effects of all three lectins. For gammaretroviruses, CV-N inhibited entry mediated by some but not all of the envelopes examined, whereas GRFT and SVN displayed only little or no effect.


Assuntos
Proteínas de Bactérias/farmacologia , Proteínas de Transporte/farmacologia , Gammaretrovirus/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Lectinas/farmacologia , Lectinas de Plantas/farmacologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus/efeitos dos fármacos , Gammaretrovirus/efeitos dos fármacos , Glicosilação , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Humanos , Proteínas de Membrana
3.
J Virol ; 87(16): 9344-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23785214

RESUMO

Human T lymphotropic virus type 1 (HTLV-1) mainly causes adult T cell leukemia and predominantly immortalizes/transforms CD4(+) T cells in culture. HTLV-2 is aleukemic and predominantly immortalizes/transforms CD8(+) T cells in culture. We have shown previously that the viral envelope is the genetic determinant of the differential T cell tropism in culture. The surface component (SU) of the HTLV-1 envelope is responsible for binding to the cellular receptors for entry. Here, we dissect the HTLV-1 SU further to identify key domains that are involved in determining the immortalization tropism. We generated HTLV-1 envelope recombinant virus containing the HTLV-2 SU domain. HTLV-1/SU2 was capable of infecting and immortalizing freshly isolated peripheral blood mononuclear cells in culture. HTLV-1/SU2 shifted the CD4(+) T cell immortalization tropism of wild-type HTLV-1 (wtHTLV-1) to a CD8(+) T cell preference. Furthermore, a single amino acid substitution, N195D, in HTLV-1 SU (Ach.195) resulted in a shift to a CD8(+) T cell immortalization tropism preference. Longitudinal phenotyping analyses of the in vitro transformation process revealed that CD4(+) T cells emerged as the predominant population by week 5 in wtHTLV-1 cultures, while CD8(+) T cells emerged as the predominant population by weeks 4 and 7 in wtHTLV-2 and Ach.195 cultures, respectively. Our results indicate that SU domain independently influences the preferential T cell immortalization tropism irrespective of the envelope counterpart transmembrane (TM) domain. We further showed that asparagine at position 195 in HTLV-1 SU is involved in determining this CD4(+) T cell immortalization tropism. The slower emergence of the CD8(+) T cell predominance in Ach.195-infected cultures suggests that other residues/domains contribute to this tropism preference.


Assuntos
Linfócitos T CD4-Positivos/virologia , Transformação Celular Viral , Produtos do Gene env/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Proteínas Oncogênicas de Retroviridae/metabolismo , Tropismo Viral , Fatores de Virulência/metabolismo , Substituição de Aminoácidos , Células Cultivadas , Análise Mutacional de DNA , Produtos do Gene env/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Oncogênicas de Retroviridae/genética
4.
Mol Cell Neurosci ; 47(1): 53-60, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21397028

RESUMO

Compensatory replacement of neurons by endogenous subventricular zone (SVZ)-derived neural precursor cells has been demonstrated in the adult brain following striatal cell loss. Such cell replacement is associated with increased SVZ cell proliferation and neuroblast expansion in the rostral migratory stream (RMS). SVZ-derived neural precursor cells co-express multiple transcription factors involved in lineage restriction and cell fate determination. We propose that compensatory neurogenesis in response to striatal cell loss will alter the temporal expression of transcription factors in discrete populations of SVZ-derived neural precursor cells. We therefore examined the expression of Mash1, Dlx2, Pax6 and Olig2 in SVZ-derived neural precursor cell populations across a range of times following quinolinic acid (QA) induced striatal cell death. We have identified a heterogeneous population of SVZ-derived neural precursor cells that respond independently to striatal cell loss. In both the anterior SVZ (aSVZ) and RMS we observed an increase in a sub-population of Dlx2+ transit amplifying precursor (TAP) cells and neuroblasts following QA lesioning when compared to controls. Subsequently, the number of Pax6+ TAPs and neuroblasts in the QA lesioned aSVZ and RMS was also increased. Olig2 expression was not however altered in response to QA-induced cell loss. Our results suggest Dlx2 and Pax6 may play a prominent role in directing neural precursor cell proliferation and neuroblast generation following striatal cell loss. Selective alteration of specific transcription factors in the SVZ and during migration through the RMS in response to cell loss may predetermine the subsequent generation of specific neuronal subclasses for endogenous replacement.


Assuntos
Corpo Estriado/citologia , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/patologia , Fatores de Transcrição Box Pareados/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Corpo Estriado/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Masculino , Células-Tronco Neurais/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fator de Transcrição PAX6 , Ácido Quinolínico/farmacologia , Ratos , Ratos Wistar , Fatores de Transcrição/genética
5.
J Cell Biochem ; 112(6): 1467-74, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21503952

RESUMO

The presence of both neural and glial precursor cells in the adult central nervous system (CNS) and the capacity of these cells to migrate through this mature structure to areas of pathological damage and injury raises hope for the development of new therapeutic strategies to treat brain injury and disease. Although at present time, the compensatory neurogenesis described after various types of brain pathologies appears to be modest, the development of a strategy promoting the directed mobilization and phenotypic induction of endogenous precursor cells to areas of neural cell loss remains of high interest. The development of such a strategy however is currently thwarted by a limited understanding of the process and factors influencing precursor cell migration. In this review, we will discuss the current knowledge around precursor cell migration in the pathological adult brain with particular focus on the response and fate of precursor sub-populations to neural cell loss and the role of the inflammatory system in mediating precursor cell migration. Through this discussion we will identify particular areas in which further detailed research is required in order to expand our current understanding and aid in the eventual development of a novel therapeutic application.


Assuntos
Encéfalo/citologia , Movimento Celular/fisiologia , Células-Tronco Neurais/citologia , Animais , Humanos , Mamíferos , Neurogênese/fisiologia
6.
J Virol ; 84(6): 3043-58, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20071587

RESUMO

Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIV(mac251)-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIV(mac251) demonstrated comparable levels of SIV(mac251) viral replication, similar rates of mucosal and peripheral CD4(+) T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIV(mac251) coinfected animals versus SIV(mac251) singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIV(mac251) infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIV(mac251) infection.


Assuntos
Infecções por HTLV-II/imunologia , Vírus Linfotrópico T Tipo 2 Humano/imunologia , Macaca mulatta/virologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Genoma Viral , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Ativação Linfocitária/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Carga Viral
7.
Blood ; 113(21): 5176-85, 2009 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-19270265

RESUMO

Human T-cell lymphotropic virus type 1 (HTLV-1) entry involves the interaction between the surface (SU) subunit of the Env proteins and cellular receptor(s). Previously, our laboratories demonstrated that heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), a receptor of VEGF(165), are essential for HTLV-1 entry. Here we investigated whether, as when binding VEGF(165), HSPGs and NRP-1 work in concert during HTLV-1 entry. VEGF(165) binds to the b domain of NRP-1 through both HSPG-dependent and -independent interactions, the latter involving its exon 8. We show that VEGF(165) is a selective competitor of HTLV-1 entry and that HTLV-1 mimics VEGF(165) to recruit HSPGs and NRP-1: (1) the NRP-1 b domain is required for HTLV-1 binding; (2) SU binding to target cells is blocked by the HSPG-binding domain of VEGF(165); (3) the formation of Env/NRP-1 complexes is enhanced by HSPGs; and (4) the HTLV SU contains a motif homologous to VEGF(165) exon 8. This motif directly binds to NRP-1 and is essential for HTLV-1 binding to, internalization into, and infection of CD4(+) T cells and dendritic cells. These findings demonstrate that HSPGs and NRP-1 function as HTLV-1 receptors in a cooperative manner and reveal an unexpected mimicry mechanism that may have major implications in vivo.


Assuntos
Proteoglicanas de Heparan Sulfato/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Neuropilina-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ligação Viral , Ligação Competitiva , Células Cultivadas , Produtos do Gene env/metabolismo , Infecções por HTLV-I/virologia , Humanos , Mimetismo Molecular , Ligação Proteica , Receptores Virais/metabolismo
8.
Retrovirology ; 7: 99, 2010 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-21114861

RESUMO

The identity of the Human T lymphotropic Virus type 1 (HTLV-1) receptor remained an unsolved puzzle for two decades, until the recent demonstration that three molecules, Glucose Transporter 1, Neuropilin-1 and Heparan Sulfate Proteoglycans are involved in HTLV-1 binding and entry. Despite these advances, several questions remain unanswered, including the precise role of each of these molecules during virus entry. In light of the most recent data, we propose a model of the HTLV-1 receptor complex and discuss its potential impact on HTLV-1 infection.


Assuntos
Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Receptores Virais/metabolismo , Transportador de Glucose Tipo 1/fisiologia , Proteoglicanas de Heparan Sulfato/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Neuropilina-1/fisiologia , Ligação Viral
9.
J Virol ; 83(10): 5244-55, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19279090

RESUMO

Little is known about the transmission or tropism of the newly discovered human retrovirus, human T-cell lymphotropic virus type 3 (HTLV-3). Here, we examine the entry requirements of HTLV-3 using independently expressed Env proteins. We observed that HTLV-3 surface glycoprotein (SU) binds efficiently to both activated CD4(+) and CD8(+) T cells. This contrasts with both HTLV-1 SU, which primarily binds to activated CD4(+) T cells, and HTLV-2 SU, which primarily binds to activated CD8(+) T cells. Binding studies with heparan sulfate proteoglycans (HSPGs) and neuropilin-1 (NRP-1), two molecules important for HTLV-1 entry, revealed that these molecules also enhance HTLV-3 SU binding. However, unlike HTLV-1 SU, HTLV-3 SU can bind efficiently in the absence of both HSPGs and NRP-1. Studies of entry performed with HTLV-3 Env-pseudotyped viruses together with SU binding studies revealed that, for HTLV-1, glucose transporter 1 (GLUT-1) functions at a postbinding step during HTLV-3 Env-mediated entry. Further studies revealed that HTLV-3 SU binds efficiently to naive CD4(+) T cells, which do not bind either HTLV-1 or HTLV-2 SU and do not express detectable levels of HSPGs, NRP-1, and GLUT-1. These results indicate that the complex of receptor molecules used by HTLV-3 to bind to primary T lymphocytes differs from that of both HTLV-1 and HTLV-2.


Assuntos
Antígenos de Deltaretrovirus/metabolismo , Deltaretrovirus/metabolismo , Produtos do Gene env/metabolismo , Receptores Virais/metabolismo , Sequência de Aminoácidos , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Linhagem Celular , Deltaretrovirus/genética , Deltaretrovirus/fisiologia , Transportador de Glucose Tipo 1/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Dados de Sequência Molecular , Filogenia , Ligação Proteica , Alinhamento de Sequência , Transdução Genética , Ligação Viral
10.
Neurogenesis (Austin) ; 4(1): 1-5, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28596976

RESUMO

Adult human neurogenesis has generated excitement over the last 2 decades with the idea that endogenous adult stem cells could act as a potential cell source for brain repair after injury. Indeed, many forms of experimentally induced brain injury including stroke and excitotoxic lesioning can promote proliferation from the subventricular zone and mobilise neuroblasts and oligodendrocyte progenitor cells to migrate through brain parenchyma to damaged regions. However the failure of neuroblasts to mature into appropriate neuronal subtypes for cell replacement has been an issue. Recent work by our group and others has indicated that micro-environmental signals released from areas of cell loss may be able to override intrinsic gene expression lineages and covert neuroblasts into oligodendrocyte progenitor cells. This commentary will discuss the enhanced fate plasticity of both adult neural progenitors and parenchymal NG2 cells after injury, and the importance of understanding brain-injury induced micro-environmental signals in the quest toward promoting endogenous regeneration after injury.

11.
J Stem Cells Regen Med ; 12(1): 25-35, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27397999

RESUMO

Despite the presence of on-going neurogenesis in the adult mammalian brain, neurons are generally not replaced after injury. Using a rodent model of excitotoxic cell loss and retroviral (RV) lineage tracing, we previously demonstrated transient recruitment of precursor cells from the subventricular zone (SVZ) into the lesioned striatum. In the current study we determined that these cells included migratory neuroblasts and oligodendrocyte precursor cells (OPC), with the predominant response from glial cells. We attempted to override this glial response by ectopic expression of the pro-neurogenic genes Pax6 or Dlx2 in the adult rat SVZ following quinolinic acid lesioning. RV-Dlx2 over-expression stimulated repair at a previously non-neurogenic time point by enhancing neuroblast recruitment and the percentage of cells that retained a neuronal fate within the lesioned area, compared to RV-GFP controls. RV-Pax6 expression was unsuccessful at inhibiting glial fate and intriguingly, increased OPC cell numbers with no change in neuronal recruitment. These findings suggest that gene choice is important when attempting to augment endogenous repair as the lesioned environment can overcome pro-neurogenic gene expression. Dlx2 over-expression however was able to partially overcome an anti-neuronal environment and therefore is a promising candidate for further study of striatal regeneration.

12.
AIDS Res Hum Retroviruses ; 21(1): 43-50, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15665643

RESUMO

Cholesterol-rich plasma membrane microdomains are important for entry of many viruses, including retroviruses. Depletion of cholesterol with 2-hydroxypropyl-beta-cyclodextrin inhibits entry of human T cell leukemia virus type I (HTLV-1) and HTLV-I envelope pseudotyped lentivirus particles. Using a soluble fusion protein of the HTLV-I surface envelope protein with the immunoglobulin Fc domain, the HTLV-I receptor was found to colocalize with a raft-associated marker and to cluster in specific plasma membrane microdomains. Depletion of cholesterol did not alter receptor binding activity, suggesting a requirement for cholesterol in a postbinding virus entry step.


Assuntos
Colesterol/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Microdomínios da Membrana/metabolismo , Vírion/patogenicidade , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Linhagem Celular , Membrana Celular/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Lentivirus/genética , Receptores Virais/metabolismo , Transfecção , Proteínas do Envelope Viral , Vírion/genética , Vírion/metabolismo , beta-Ciclodextrinas
14.
Stem Cells Transl Med ; 2(8): 579-83, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23817132

RESUMO

Since induced pluripotent stem cells were first generated from mouse embryonic fibroblasts in 2006, somatic cell reprogramming has become a powerful and valuable tool in many fields of biomedical research, with the potential to lead to the development of in vitro disease models, cell-based drug screening platforms, and ultimately novel cell therapies. Recent research has now demonstrated the direct conversion of fibroblasts into stem, precursor, or mature cell types that are committed in their fate within a specific lineage, such as hematopoietic precursors or mature neurons. This has been achieved by ectopic expression of defined, tissue-specific transcription factors. Several studies have demonstrated direct reprogramming of mouse and human fibroblasts into immature neural stem or precursor cells, either by transient expression of the four pluripotency genes OCT3/4, KLF4, SOX2, and C-MYC or by application of different combinations of up to 11 neural transcription factors. Interestingly, in all of these studies SOX2 was introduced alone or in combination with other transcription factors. In this review we discuss the different combinations of ectopic transcription factors used to generate neural stem/precursor cells from somatic cells, with particular emphasis on SOX2 and its potential to act as a master regulator for reprogramming to a neural precursor state.


Assuntos
Reprogramação Celular , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Animais , Reprogramação Celular/genética , Regulação da Expressão Gênica , Humanos , Fator 4 Semelhante a Kruppel , Modelos Biológicos
15.
Front Microbiol ; 3: 378, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23109932

RESUMO

The deltaretroviruses human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2) have long been believed to differ from retroviruses in other genera by their mode of transmission. While other retroviruses were thought to primarily spread by producing cell-free particles that diffuse through extracellular fluids prior to binding to and infecting target cells, HTLV-1 and HTLV-2 were believed to transmit the virus solely by cell-cell interactions. This difference in transmission was believed to reflect the fact that, relative to other retroviruses, the cell-free virions produced by HTLV-infected cells are very poorly infectious. Since HTLV-1 and HTLV-2 are primarily found in T cells in the peripheral blood, spread of these viruses was believed to occur between infected and uninfected, T cells, although little was known about the cellular and viral proteins involved in this interaction. Recent studies have revealed that the method of transmission of HTLV is not unique: other retroviruses including human immunodeficiency virus (HIV) are also transmitted from cell-to-cell, and this method is dramatically more efficient than cell-free transmission. Moreover, cell-cell transmission of HTLV-1, as well as HIV, can occur following interactions between dendritic cells and T cells, as well as between T cells. Conversely, other studies have shown that cell-free HTLV-1 is not as poorly infectious as previously thought, since it is capable of infecting certain cell types. Here we summarize the recent insights about the mechanisms of cell-cell transmission of HTLV-1 and other retroviruses. We also review in vitro and in vivo studies of infection and discuss how these finding may relate to the spread of HTLV-1 between individuals.

16.
Am J Stem Cells ; 1(1): 48-58, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23671797

RESUMO

Regulation over the generation of adult born neuroblasts and oligodendrocyte precursor cells is governed by a myriad of extracellular signals. These signals must be related into the cell nucleus to regulate cell cycle and cell lineage maturation programmes. This internal regulation is controlled by proneural and anti-neurogenic transcription factors, including Mash1, Pax6, Dlx2 and Olig2. This review will cover how transcription factors regulate adult SVZ neurogenesis; the progression from neural stem cell, to transit amplifying precursor cell, to neuroblast or oligodendrocyte precursor cell, and how transcription factors influence neuronal subtype specification. Changes to transcriptional regulation that occur after brain injury and what this means for endogenous brain repair strategies will also be covered.

18.
Viruses ; 3(6): 794-810, 2011 06.
Artigo em Inglês | MEDLINE | ID: mdl-21994754

RESUMO

The initial step in retroviral infection involves specific interactions between viral envelope proteins (Env) and specific receptors on the surface of target cells. For many years, little was known about the entry receptors for HTLV-1. During this time, however, functional domains of the HTLV-1 Env were identified by analyzing the effects of neutralizing antibodies and specific mutations in Env on HTLV-1 infectivity. More recent studies have revealed that HTLV-1 infectivity involves interactions with three different molecules: heparan sulfate proteoglycans (HSPG), the VEGF-165 receptor Neuropilin 1 (NRP-1) and glucose transporter type 1 (GLUT1). Here, we revisit previously published data on the functional domains of Env in regard to the recent knowledge acquired about this multi-receptor complex. We also discuss the similarities and differences between HTLV-1 and other deltaretroviruses in regards to receptor usage.


Assuntos
Produtos do Gene env/química , Produtos do Gene env/metabolismo , Infecções por HTLV-I/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Receptores Virais/metabolismo , Internalização do Vírus , Animais , Produtos do Gene env/genética , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/química , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Estrutura Terciária de Proteína , Receptores Virais/genética
19.
Nat Med ; 14(4): 429-36, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18376405

RESUMO

Cell-free human T-lymphotropic virus type 1 (HTLV-1) virions are poorly infectious in vitro for their primary target cells, CD4(+) T cells. Here, we show that HTLV-1 can efficiently infect myeloid and plasmacytoid dendritic cells (DCs). Moreover, DCs exposed to HTLV-1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4(+) T cells. This DC-mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long-term productive infection and interleukin-2-independent transformation of the CD4(+) T cells. These studies, along with observations of HTLV-1-infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV-1 infection plays a part in pathogenesis.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Comunicação Celular , Linhagem Celular , Transformação Celular Viral , Sistema Livre de Células , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/transmissão , Infecções por HTLV-I/virologia , Proteoglicanas de Heparan Sulfato/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Imunofilinas/imunologia , Técnicas In Vitro , Ativação Linfocitária
20.
J Virol ; 81(3): 1506-10, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17108050

RESUMO

GLUT1 has recently been suggested to be a binding receptor for human T-cell leukemia virus type 1 (HTLV-1). We used a novel, short-term assay to define the role of GLUT1 in cell-to-cell transmission. Although increasing cell surface levels of GLUT1 enhanced HTLV-I transfer, efficient virus spread correlated largely with heparan sulfate proteoglycan (HSPG) expression on target cells. Moreover, since activated CD4+ T cells and cord blood lymphocytes that are susceptible to HTLV-1 infection expressed undetectable levels of surface GLUT1, these results indicate that GLUT1 and HSPGs are important for efficient cell-to-cell transmission of HTLV-1 but raise concerns on the role of GLUT1 as the HTLV-1 primary binding receptor.


Assuntos
Transportador de Glucose Tipo 1/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Receptores Virais/metabolismo , Vírion/fisiologia , Infecções por HTLV-I/transmissão , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Leucemia de Células T/fisiopatologia , Leucemia de Células T/virologia
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