Entry of Human T-Cell Leukemia Virus Type 1 Is Augmented by Heparin Sulfate Proteoglycans Bearing Short Heparin-Like Structures

Abstract

bThree molecules have been identified as the main cellular factors required for binding and entry of human T-cell leukemia virus type 1 (HTLV-1): glucose transporter 1 (GLUT1), heparan sulfate (HS), and neuropilin 1 (NRP-1). However, the precise mechanism of HTLV-1 cell tropism has yet to be elucidated. Here, we examined the susceptibilities of various human cell lines to HTLV-1 by using vesicular stomatitis virus pseudotypes bearing HTLV-1 envelope proteins. We found that the cellular susceptibility to HTLV-1 infection did not correlate with the expression of GLUT1, HS, or NRP-1 alone. To investigate whether other cellular factors were responsible for HTLV-1 susceptibility, we conducted expression cloning. We identified two HS proteoglycan core proteins, syndecan 1 and syndecan 2, as molecules responsible for susceptibility to HTLV-1. We found that treatment of syndecan 1-transduced cells (expressing increased HS) with heparinase, a heparin-degradative enzyme, reduced HTLV-1 susceptibility without affecting the expression levels of HS chains. To further elucidate these results, we characterized the expression of HS chains in terms of the mass, number, and length of HS in several syndecan 1-transduced cell clones as well as human cell lines. We found a significant correlation between HTLV-1 susceptibility and the number of HS chains with short chain lengths. Our findings suggest that a combination of the number and the length of HS chains containing heparin-like regions is a critical factor which affects the cell tropism of HTLV-1. Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (16, 49) and HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (10,24,45). Previous investigations revealed that HTLV-1 infects not only human T lymphocytes and central nervous system cells but also cells of other tissues (6,17,21,34,51,69). To date, glucose transporter 1 (GLUT1), neuropilin-1 (NRP-1), and heparan sulfate proteoglycans (HSPGs) have been implicated as being involved in HTLV-1 infection (reviewed in reference 12). The expression of GLUT1, which is responsible for viral binding and fusion mediated by the gp46 surface envelope (Env) protein (3,26,39), is ubiquitous, and it is also known that various cells express HSPGs. Although these findings might be able to explain the broad host cell range of HTLV-1, they are not sufficient to explain the variance of HTLV-1 cell tropism.It was previously reported that HTLV-1 spreads from cell to cell via virological synapses (22, 38); however, recent studies by Pais-Correia and colleagues showed that the HTLV-1 virions retaining extracellular structures are important for HTLV-1 cell transmission (46). That study implied that the viral particle mediates HTLV-1 transmission and suggested the importance of the interaction between viral particles and the target cell surface. In this study, we investigated the susceptibilities of various human cell lines to cell-free HTLV-1 infection using highly infectious vesicular stomatiti...

Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection

“…Interestingly, the R&D Glut1 antibody detected intra-cellular but not cell surface Glut1 in NIH3T3 cells that were overexpressing Glut1, an observation that is not consistent with the suggestion that the antibody interacts with a different cell surface protein that is associated with Glut-1 overexpression in transformed cells [32]. More recently, this antibody has been shown by others to be specific for Glut1 [40] and has been used to evaluate Glut1 expression on cell surfaces [28,29] including T cells in a cohort of HIV-infected individuals [30]. We have also clearly shown increased intracellular Glut1 (using a Glut-1 cterm antibody), increased Glut1 mRNA, and increased glucose uptake in CD4 + T cells in HIV+/naive individuals, all of which is consistent with increased glucose metabolic activity.…”

Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission

“…Since cell-cell contacts are a prerequisite for efficient HTLV-1 transmission, it is reasonable that cell surface receptors are critical for this step. Not only receptors on the target cells—like components of the HTLV-1 receptor (Glut-1, NRP-1, HSPGs, SDC-1/-2)—are important for viral transmission and tropism [ 18 , 117 ], but also secreted chemokines that could attract target cells. To attract CCR4 + CD4 + target T-cells, Tax expressing HTLV-1-infected T-cells produce large amounts of CCL22.…”

Heparan Sulfate Is an Attachment Factor for Foamy Virus Entry

“…A review by Liu and Thorp lists 16 animal and human viruses that use HS as a receptor for attachment or entry (24), including human T-cell leukemia virus (HTLV) (20,31,46), HIV (11,26,29,38,50), herpes simplex virus (49), cytomegalovirus (9), dengue virus (8), adeno-associated virus type 2 (43), and respiratory syncytial virus (14).…”