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HTLV-1 sweet-talks its way into cells
The first infectious human retrovirus to be identified, before we even imagined the devastation of HIV, was human T-lymphotropic virus type 1 (HTLV-1)1. HTLV-1 causes disease—mainly adult T-cell lymphoma or leukemia or HTLV-1-associated myelopathy—in only small fraction of infected individuals. The virus, however, cuts a wide swath, infecting about 10–20 million people worldwide by spreading from person to person through infected cells in semen, blood and breast milk. Despite years of effort, the identity of the receptor that facilitates the spread of HTLV-1 has remained elusive. In a recent issue of Cell, Manel et al. provide evidence that GLUT-1, a ubiquitous glucose transport protein, is a receptor for HTLV-1 (ref. 2).
Most retroviral receptors have been cloned by transferring a library of sequences from a cell line that is permissive for entry, and therefore expresses the receptor, into one that is nonpermissive. A marked version of the virus can then be used to specifically select cells with the receptor gene from cells that acquired irrelevant cellular sequences. HTLV-1 infects most cell lines but is found primarily in lymphocytes, including lymphoma cells, in infected patients. The paucity of nonpermissive cell lines, as well as difficulties in making high titers of marked virus, has foiled attempts at conventional receptor cloning strategies. For these reasons, Manel et al. used a clever deductive approach that relied on several clues to identify a receptor candidate.
The first clue was that cells expressing the HTLV-1 envelope protein, which binds the receptor and initiates entry, showed perturbations in lactate and glucose metabolism—namely, delayed acidification of the cell culture medium. This observation implicated a receptor involved in lactate or glucose transport. Because many known retroviral receptor proteins are transporters3, a transport protein has always been a strong contender for the HTLV-1 receptor.
Another crucial clue came from HTLV-1 envelope binding studies, which suggested that the receptor was expressed very early after lymphocyte activation, and that its temporal pattern of expression was distinct from that of many other activation markers4, 5. Together, these clues led the authors to GLUT-1, a member of a family of glucose transport proteins.
The tactic of finding a receptor to meet the authors' criteria, rather than letting the virus select the receptor in a functional screen, carries with it a considerable burden of proof. The authors used several lines of evidence to support their case. Binding studies demonstrated a direct interaction between the HTLV-1 envelope and GLUT-1, but not other related transport proteins. Downmodulating GLUT-1 led to reduced HTLV-1 binding and infection, whereas increasing GLUT-1 expression restored these outcomes. Finally, the authors provided data that GLUT-1 is a receptor for a related, relatively avirulent retrovirus, HTLV-2, fulfilling predictions from previous studies6. Collectively, the results provide a compelling case for GLUT-1 as an HTLV-1 receptor (Fig. 1). Left unresolved is whether GLUT-1 can render a normally nonpermissive cell susceptible to HTLV-1 infection, a challenging experiment given the limited availability of suitable nonpermissive cells.
The molecular characterization of the HTLV-1 receptor should provide a powerful tool for understanding the complexities of HTLV-1 pathogenesis. Viruses often do not cause disease through direct interactions with their receptors. In fact, retroviruses may converge on transport proteins as receptors, in part because these transporters tend to be redundant, and using them often does not immediately harm the cell. GLUT-1 could be an exception because, as noted by Manel et al., metabolic perturbations occur after the HTLV-1 envelope binds the receptor2.
The difference in host cell specificities of HTLV-1 in patients and in culture remains puzzling, as do observations that HTLV-1 and HTLV-2 share a common receptor but are found in different cell types in infected patients. The cell targets of HTLV-1 and HTLV-2 have not been rigorously characterized throughout all stages of infection in people; this could be done in concert with an examination of GLUT-1 expression. A finding that HTLV-1 infection is limited to only a subset of GLUT-1-expressing cells may suggest that a second receptor molecule fine-tunes host cell specificity, as has been seen for HIV-1 and a lymphotropic feline leukemia virus3.
The studies of Manel et al. and others specifically focused on viral entry because they relied heavily on HTLV-1 pseudotypes—particles with the core and inner workings of another virus and the HTLV-1 envelope on the surface (Fig. 1a). It is possible, therefore, that the ubiquitous GLUT-1 receptor permits HTLV-1 entry into many cell types, but another barrier to productive infection after entry further limits the types of cells that are susceptible to HTLV-1. Because such postentry restrictions have been observed for oncogenic retroviruses (such as murine leukemia virus) and lentiviruses (such as HIV)7, it is reasonable to expect that similar host cell barriers might thwart the replication of HTLV-1 in certain cell types (Fig. 1b). Replication studies using HTLV-1, rather than pseudotyped viruses, could address this possibility.
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作者:admin@医学,生命科学 2011-02-13 17:11
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