HTLV-2 binding and entry also involves NRP-1 and GLUT1, but differs from HTLV-1 in that it does not require HSPG. Efficient entry of HTLV-1 has been shown to involve three distinct molecules: heparan sulfate proteoglycans (HSPGs) and Neuropilin 1 (NRP-1) for the initial binding to the cell, and glucose transporter 1 (GLUT1) for entry ( Manel et al., 2003 Jones et al., 2005 Ghez et al., 2006 Lambert et al., 2009). Like other retroviruses, HTLV-1 and HTLV-2 enter target cells following specific interactions between the viral envelope glycoprotein (Env) and cellular receptors. Dendritic cells (DCs), B cells, and monocytes can also be infected in individuals with HTLV ( Macatonia et al., 1992 Koyanagi et al., 1993). ATL is a malignancy of CD4 + T cells, and HTLV-1 primarily infects CD4 + T cells, while HTLV-2 primarily infects CD8 + T cells ( Kira et al., 1991 Lal et al., 1995 Wu et al., 1996 Manns et al., 1999 Nagai et al., 2001 Murphy et al., 2004). In the peripheral blood of infected individuals, both HTLV-1 and HTLV-2 are primarily found in T cells, and both viruses can immortalize T cells in culture (reviewed in Feuer and Green, 2005). The closely related retrovirus human T cell leukemia virus type 2 (HTLV-2) does not cause leukemia, although some infected individuals develop mild lymphocytosis and, occasionally, neurologic symptoms ( Hjelle et al., 1992 Dooneief et al., 1996 Feuer and Green, 2005 Biswas et al., 2009). HTLV-1 is also associated with several inflammatory disorders, primarily a progressive neurological disease named HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP Gessain et al., 1985 Osame et al., 1986). This virus is the only human retrovirus known to be the causal agent of a cancer, a neoplasia called adult T cell leukemia (ATL Yoshida et al., 1982, 1984). Human T cell lymphotropic virus type 1 (HTLV-1) was the first pathogenic retrovirus discovered in humans ( Poiesz et al., 1980). 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. Here we summarize the recent insights about the mechanisms of cell–cell transmission of HTLV-1 and other retroviruses. 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. 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. 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. 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. 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. 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. 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. 2Cancer and Inflammation Program, Basic Research Program, SAIC-Frederick, Inc., Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.1CNRS UMR 8104, INSERM U567, Université Paris-Descartes, Institut Cochin, Paris, France.
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