Infection of CD4+ T lymphocytes by the human T cell leukemia virus type 1 is mediated by the glucose transporter GLUT-1: Evidence using antibodies specific to the receptor's large extracellular domain

Qi, Jin; Agrawal, Lokesh; VanHorn-Ali, Zainab; Alkhatib, Ghalib

doi:10.1016/j.virol.2006.01.045

Cited by 28 publications

(28 citation statements)

References 33 publications

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“…Formation of a virological synapse, polarization of the cytoskeleton, and passage of HTLV-1 virions have been observed during contact between infected and noninfected T cells (5). Although the precise mechanism of HTLV-1 virion transfer remains elusive, several recent studies have suggested that the glucose transporter 1 (GLUT1) can function as a receptor for HTLV (2,13) as well as participate in Env-mediated cellcell fusion (2,7). However, it is still unclear whether GLUT1 is important for cell-to-cell transmission of HTLV-1.…”

Section: The Human T-cell Leukemia Virus Type I (Htlv-1) (19) Ismentioning

confidence: 99%

GLUT1 Is Not the Primary Binding Receptor but Is Associated with Cell-to-Cell Transmission of Human T-Cell Leukemia Virus Type 1

Takenouchi

Jones

Lisinski

et al. 2007

J Virol

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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.The human T-cell leukemia virus type I (HTLV-1) (19) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (3,17,23). Efficient transmission of HTLV-1 is believed to require contact between cells. Cell-free HTLV-1 virions are very poorly infectious. Formation of a virological synapse, polarization of the cytoskeleton, and passage of HTLV-1 virions have been observed during contact between infected and noninfected T cells (5). Although the precise mechanism of HTLV-1 virion transfer remains elusive, several recent studies have suggested that the glucose transporter 1 (GLUT1) can function as a receptor for HTLV (2, 13) as well as participate in Env-mediated cellcell fusion (2, 7). However, it is still unclear whether GLUT1 is important for cell-to-cell transmission of HTLV-1. To address this question, we have adapted methods to express and detect GLUT1 on the surface of target cells that express low levels of endogenous cell surface GLUT1. COS-7 cells were transfected with an expression vector encoding GLUT1 and an extracellular hemagglutinin (HA) tag (HA-GLUT1). A mutant form of glucose transporter 6, which also contains HA tag (HA-GLUT6M) and the parental vector (pCIS) were used as controls (1, 11). Both HA-GLUT1 and HA-GLUT6M were expressed at high levels on the cell surface (Fig. 1A, top row). Increase in cell surface GLUT expression was verified by another approach using a photoaffinity label technique (bisglucose photolabel; Bio-LC-ATB-BMPA) (4) performed as recently described (8). These studies revealed that, while the endogenous level of cell surface GLUT1 was below the detectable level of this assay (Fig. 1B, lane 2), cells transfected with HA-GLUT1 vector expressed high levels of GLUT1 on the cell surface (Fig. 1B, lane 4). In addition, a significant amount of endogenous intracellular GLUT1 could be detected in the total cell lysate from both the nontransfected and transfected cells by standard Western blotting (Fig. 1B, lanes 5 and 6).We next determined the effect of GLUT1 overexpression on cell-to-cell transmission of HTLV-1 virions. The HTLV-1-producing CD4 ϩ T-cell line was cocultured with target cells transfected with pCIS, HA-GLUT1, or HA-GLUT6M expression vectors. After 2 days of coculturing, the target cells were immunostaine...

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Section: The Human T-cell Leukemia Virus Type I (Htlv-1) (19) Ismentioning

confidence: 99%

GLUT1 Is Not the Primary Binding Receptor but Is Associated with Cell-to-Cell Transmission of Human T-Cell Leukemia Virus Type 1

Takenouchi

Jones

Lisinski

et al. 2007

J Virol

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“…HTLV-1 can be transmitted from mother to child, during sexual intercourse, and through contaminated blood products 7 . HTLV-1 has a special tropism for CD4+ lymphocytes and uses GLUT-1, the ubiquitous vertebrate glucose transporter, as the main receptor to infect cells 8 . It is trans-mitted from cell to cell through a viral synapse and enters target cells via interaction with GLUT-1 in association with Neuropilin-1 (NRP1), the receptor for semaphorin-3A, and VEGF-A165, a member of the immune synapse.…”

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confidence: 99%

HTLV-1 and neurological conditions: when to suspect and when to order a diagnostic test for HTLV-1 infection?

Araújo

Leite

Lima

et al. 2009

Arq. Neuro-Psiquiatr.

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-HTLV-1 is a retrovirus associated with a myriad of clinical conditions, especially hematological and neurological ones. Regarding nervous system diseases, it is of utmost importance to select those cases in which HTLV-1 infection could really be associated. This is particularly true for patients from endemic areas and for HIV-infected patients and drug users, since that these groups are at a higher risk for HTLV infection. This caution in selecting neurological patients for HTLV diagnostic tests is justified by the fact that in some circumstances the seropositivity may merely represent an epiphenomenon. In this paper we enroll some neurological conditions that have been associated with HTLV-1/2 infection in the literature and discuss the real need for HTLV-1/2 diagnostic tests in each one. Because HIV/HTLV-co-infected patients seem to be at an increased risk for neurological diseases development, a special consideration about this matter is also made.KEy WORDs: HTLV, myelopathy, myopathy, peripheral neuropathy, HIV.doenças neurológicas e infecção pelo HTLV-1: quando suspeitar e quando solicitar testes diagnósticos para a infecção pelo HTLV-1Resumo -O HTLV-1 é um retrovírus associado tanto a doenças hematológicas quanto a doenças neurológicas. Em relação às doenças neurológicas, é fundamental que selecionemos aquelas em que de fato a infecção pelo HTLV-1 possa ser a causa. Isto é particularmente verdadeiro nos pacientes oriundos de áreas endêmicas e nos pacientes infectados pelo HIV e usuários de drogas, haja vista que estes grupos são de risco para infecção pelo HTLV. Este cuidado ao selecionarmos aquelas condições neurológicas que merecem ser investigadas com sorologia para o HTLV se justifica pelo fato de que nem sempre podemos afastar uma associação fortuita entre a infecção e a referida doença. Neste artigo, comentaremos sobre algumas condições neurológicas que podem estar associadas com a infecção pelo HTLV-1/2, discutindo a real necessidade de solicitar testes para o diagnóstico da infecção pelo HTLV-1/2 frente a elas. Uma breve consideração sobre a co-infecção HIV/ HTLV será feita no final deste artigo tendo em vista que estes pacientes apresentam um risco aumentado para o desenvolvimento de doenças neurológicas.PALAVRAs-CHAVE: HTLV, mielopatia, miopatia, neuropatia periférica, HIV.The human T cell lymphotropic virus type 1 (HTLV-1) is a retrovirus and the etiologic agent of both a group of hematological disorders known as Adult T cell leukemia/ lymphoma (ATLL) 1 and a group of neurological conditions known altogether as the HTLV-1 neurological complex 2 , of which the most common is the HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TsP) 3 . Endemic infection with HTLV-1 is now recognized to be worldwide, and is also common in Brazil 4 . The number of people around the world infected with HTLV-1 is estimated as being between 10 to 20 million. There are areas in Japan, sub-saharan Africa, the Caribbean, and south America where more than 1% of the general population is infected. T...

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“…GLUT1 binds to HTLV-1 and HTLV-2 envelope proteins, and GLUT1 depletion in target cells reduces infection by HTLV-2-enveloped pseudotypes (36). The overexpression of GLUT1 increases the susceptibility of resistant cells to HTLV-1 Env-mediated cell fusion and infection (9), and an antibody directed to GLUT1 blocks HTLV-1 Envmediated cell fusion and infection of primary CD4 ϩ T lymphocytes (23). Mutation of residue 106 or 114 of Env reduces or abolishes the interaction of SU with GLUT1 (36), account-ing for the importance in HTLV-1 Env functions of the amino acid 100 region of the SU.…”

mentioning

confidence: 99%

Neuropilin-1 Is Involved in Human T-Cell Lymphotropic Virus Type 1 Entry

Gourichon

Lepelletier

Lambert

et al. 2006

J Virol

173

151

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Human T-cell lymphotropic virus type 1 (HTLV-1) is transmitted through a viral synapse and enters target cells via interaction with the glucose transporter GLUT1. Here, we show that Neuropilin-1 (NRP1), the receptor for semaphorin-3A and VEGF-A165 and a member of the immune synapse, is also a physical and functional partner of HTLV-1 envelope (Env) proteins. HTLV-1 Env and NRP1 complexes are formed in cotransfected cells, and endogenous NRP1 contributes to the binding of HTLV-1 Env to target cells. NRP1 overexpression increases HTLV-1 Env-dependent syncytium formation. Moreover, overexpression of NRP1 increases both HTLV-1 and HTLV-2 Env-dependent infection, whereas down-regulation of endogenous NRP1 has the opposite effect. Finally, overexpressed GLUT1, NRP1, and Env form ternary complexes in transfected cells, and endogenous NRP1 and GLUT1 colocalize in membrane junctions formed between uninfected and HTLV-1-infected T cells. These data show that NRP1 is involved in HTLV-1 and HTLV-2 entry, suggesting that the HTLV receptor has a multicomponent nature.Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (49). Unlike other retroviruses, free HTLV-1 virions are poorly infectious, with cellto-cell contact being the major route of viral transfer in vivo (14). The importance of intercellular contacts for efficient HTLV-1 transmission was highlighted by Bangham and collaborators, who showed that an essential determinant of HTLV-1 cell-cell spreading is the establishment of a viral synapse (21).On the viral side, HTLV-1 entry depends on the 46-kDa surface glycoprotein (SU), which is responsible for receptor recognition, and the 21-kDa transmembrane glycoprotein (TM), which triggers the fusion between viral and cellular membranes (32). Both proteins are produced by cleavage of the 61-kDa envelope (Env) precursor (42,46). Regions in the 313-amino-acid-long SU encompassing residues 100 and 200 were shown to be the targets of neutralizing antibodies (2,43,57). Consistent with these observations, we and others showed that mutations introduced in these regions reduce the ability of HTLV-1 Env to trigger syncytium formation and/or virus infection (11,12,48,52,59).Originally detected in CD4 ϩ T cells (50), HTLV-1 infects other cell types in vivo, including CD8 ϩ T cells, monocytes, endothelial cells, and dendritic cells (18,20,30,33). In contrast to this limited tropism in vivo, the HTLV receptor appears to be expressed in almost all cell lines. Moreover, the HTLV receptor is highly conserved in vertebrate species (41, 56). As a result of Env/receptor interactions, the HTLV-1 receptor is down-regulated or nonfunctional at the surface of chronically infected T cells (17,47). Cell fusion induced by HTLV-2, a closely related nonpathogenic retrovirus, is also prevented in chronically HTLV-1-infected T cells, demonstrating that HTLV-1 and HTLV-2 share the same receptor (55). Heparan sulfate proteoglycans have been reported to play a rol...

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Infection of CD4+ T lymphocytes by the human T cell leukemia virus type 1 is mediated by the glucose transporter GLUT-1: Evidence using antibodies specific to the receptor's large extracellular domain

Cited by 28 publications

References 33 publications

GLUT1 Is Not the Primary Binding Receptor but Is Associated with Cell-to-Cell Transmission of Human T-Cell Leukemia Virus Type 1

GLUT1 Is Not the Primary Binding Receptor but Is Associated with Cell-to-Cell Transmission of Human T-Cell Leukemia Virus Type 1

HTLV-1 and neurological conditions: when to suspect and when to order a diagnostic test for HTLV-1 infection?

Neuropilin-1 Is Involved in Human T-Cell Lymphotropic Virus Type 1 Entry

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