Viral Link to Chronic Fatigue Chronic fatigue syndrome (CFS) is a complex and debilitating disorder that is often linked to immune system dysfunction but whose cause(s) remain mysterious. Lombardi et al. (p. 585 , published online 8 October; see the Perspective by Coffin and Stoye ) now present a tantalizing new lead. In blood samples from 101 patients with well-documented CFS, over two-thirds (68) contained DNA from a recently described human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), which possesses sequence similarity to a murine leukemia virus. Cell culture assays confirmed that XMRV derived from CFS patient plasma and from T and B lymphocytes was infectious. Although the correlation with CFS is striking, whether the virus plays a causal role in the disorder remains to be determined. Interestingly, nearly 4% of the 218 healthy donors tested were positive for XMRV, which suggests that this virus—whose pathogenic potential is unknown—may be present in a significant proportion of the general population.

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.

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Studies using adherent cell lines have shown that glucose transporter-1 (GLUT-1) can function as a receptor for human T-cell leukemia virus type 1 (HTLV). In primary CD4؉ T cells, heparan sulfate proteoglycans (HSPGs) are required for efficient entry of HTLV-1. Here, the roles of HSPGs and GLUT-1 in HTLV-1 and HTLV-2 Env-mediated binding and entry into primary T cells were studied. Examination of the cell surface of activated primary T cells revealed that CD4 ؉ T cells, the primary target of HTLV-1, expressed significantly higher levels of HSPGs than CD8 ؉ T cells. Conversely, CD8 ؉ T cells, the primary target of HTLV-2, expressed GLUT-1 at dramatically higher levels than CD4 ؉ T cells. Under these conditions, the HTLV-2 surface glycoprotein (SU) binding and viral entry were markedly higher on CD8؉ T cells while HTLV-1 SU binding and viral entry were higher on CD4 ؉ T cells. Binding studies with HTLV-1/HTLV-2 SU recombinants showed that preferential binding to CD4 ؉ T cells expressing high levels of HSPGs mapped to the C-terminal portion of SU. Transfection studies revealed that overexpression of GLUT-1 in CD4 ؉ T cells increased HTLV-2 entry, while expression of HSPGs on CD8 ؉ T cells increased entry of HTLV-1. These studies demonstrate that HTLV-1 and HTLV-2 differ in their T-cell entry requirements and suggest that the differences in the in vitro cellular tropism for transformation and in vivo pathobiology of these viruses reflect different interactions between their Env proteins and molecules on CD4؉ and CD8 ؉ T cells involved in entry.Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are deltaretroviruses with similar genome structure and an overall nucleotide homology of approximately 70% (reviewed in reference 11). However, the two viruses differ in their pathobiology. HTLV-1 is the causal agent of adult T-cell leukemia and a progressive neurological disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (12,34,54). In contrast, HTLV-2 is essentially nonpathogenic, although a few cases of neurological disease in HTLV-2-infected individuals have been reported.Entry of retroviruses into target cells involves interactions between the viral envelope (Env) glycoproteins, a surface glycoprotein (SU), and a transmembrane glycoprotein (TM), and specific cell surface molecules referred to as receptors. The SU protein is involved in receptor recognition, and the TM protein triggers the fusion of the viral and cellular membranes, allowing entry of viral particles. For some retroviruses such as ecotropic murine leukemia viruses, a single molecule is sufficient for attachment and entry; for others such as human immunodeficiency virus (HIV), multiple molecules are required (37).Studies of viral interference indicate that HTLV-1, HTLV-2, and related simian viruses share a receptor (46,47). Cells from a variety of species express molecules capable of supporting HTLV-1 Env-mediated fusion. Many, but not all, cell lines can be transduced by HTLV-1 Env-pseudotyped vectors and/or can fuse wit...

DNA methylation, by regulating the transcription of genes, is a major modifier of the eukaryotic genome. DNA methyltransferases (DNMTs) are responsible for both maintenance and de novo methylation. We have reported that human immunodeficiency virus type 1 (HIV-1) infection increases DNMT1 expression and de novo methylation of genes such as the gamma interferon gene in CD4؉ cells. Here, we examined the mechanism(s) by which HIV-1 infection increases the cellular capacity to methylate genes. While the RNAs and proteins of all three DNMTs (1, 3a, and 3b) were detected in Hut 78 lymphoid cells, only the expression of DNMT1 was significantly increased 3 to 5 days postinfection. This increase was observed with either wild-type HIV-1 or an integrase (IN) mutant, which renders HIV replication defective, due to the inability of the provirus to integrate into the host genome. Unintegrated viral DNA is a common feature of many retroviral infections and is thought to play a role in pathogenesis. These results indicate another mechanism by which unintegrated viral DNA affects the host. In addition to the increase in overall genomic methylation, hypermethylation and reduced expression of the p16

Little is known about the requirements for human T-cell leukemia virus type I (HTLV-I) entry, including the identity of the cellular receptor(s). Recently, we have generated an HTLV-I surface glycoprotein (SU) immu-noadhesin, HTSU-IgG, which binds specifically to cell-surface protein(s) critical for HTLV-I-mediated entry in cell lines. Here, expression of the HTLV-I SU binding protein on primary cells of the immune system was examined. The immu-noadhesin specifically bound to adult T cells, B cells, NK cells, and macrophages. Cell stimulation dramatically increased the amount of binding, with the highest levels of binding on CD4 and CD8 T cells. Naive (CD45RA high , CD62L high) CD4 T cells derived from cord blood cells, in contrast to other primary cells and all cell lines examined, bound no detectable HTLV-I SU. However, following stimulation , the level of HTSU-IgG binding was rapidly induced (fewer than 6 hours), reaching the level of binding seen on adult CD4 T cells by 72 hours. In contrast to HTLV-I virions, the soluble HTSU-IgG did not effect T-cell activation or proliferation. When incubated with human peripheral blood mononuclear cells in a mixed leukocyte reaction, HTSU-IgG inhibited proliferation at less than 1 ng/ mL. These results indicate that cell-surface expression of the HTLV SU binding protein is up-regulated during in vitro activation and suggest a role for the HTLV-I SU binding proteins in the immuno-biology of CD4 T cells. (Blood. 2003;101: 3085-3092)

Little is known about the requirements for human T-cell leukemia virus type 1 (HTLV-1) entry, including the identity of the cellular receptor(s).Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus which is the etiological agent of a severe lymphocyte neoplasia called adult T-cell leukemia/lymphoma (ATL) (53, 77) and a progressive neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (19,48). The virus is endemic in southern Japan, the Caribbean basin, Central and South America, and portions of West Africa. HTLV-1 and the closely related human T-cell leukemia virus type 2 (HTLV-2) are uncommon in the general populations of the United States and Europe. However, one recent study revealed that HTLV is prevalent in the United States among paid blood donors, African-American health care clinic patients, Amerindians, intravenous drug users, and patients with other-than-low-grade non-Hodgkin's lymphoma (52).ATL is a malignancy of CD4 ϩ T cells. It has been generally believed that the majority of the cells infected by HTLV-1 in vivo are CD4 ϩ T cells (30, 54). However, HTLV-1 can infect all subsets of human lymphocytes in vitro, and recent studies indicate that both CD4 ϩ and CD8 ϩ T cells serve as viral reservoirs in HTLV-1-associated myelopathy/tropical spastic paraparesis patients (42). Although capable of infecting a number of different cell types, HTLV-1 is poorly infectious in both primary cells and established cell lines in vitro.As for all retroviruses, entry of HTLV-1 into target cells is mediated by the envelope glycoproteins (Env), a surface glycoprotein (SU), and a transmembrane glycoprotein (TM). The HTLV-1 Env proteins are initially synthesized as precursor proteins, which are subsequently glycosylated and cleaved in the Golgi apparatus by a furin-like cellular protease to yield the SU (gp46) and the TM (gp21) glycoproteins. Following cleavage, the SU and the TM remain associated with each other through noncovalent interactions (51). As for other retroviruses, it is believed that the HTLV-1 SU glycoprotein specifically binds to a cellular receptor, inducing a conformational change in the SU-TM complex. This change activates a fusion domain within TM, allowing fusion of the viral and cellular membranes (5,9,10,37,51,55,56). Recent work using HTLV/ murine leukemia virus (MLV) envelope chimeras strongly suggests that the region of SU that interacts with the receptor is located within the N-terminal two-thirds of the protein (29). For HTLV-1, both SU and TM appear to play an additional role in a postfusion event critical for infectivity (11,28).The cellular receptor(s) for HTLV-1 have not yet been identified. Based on results from receptor interference assays, HTLV-1 is believed to share a common receptor with HTLV-2 and other primate T-cell leukemia/lymphoma viruses (64, 55). The gene encoding the receptor was mapped to chromosome 17 and further localized to 17q23. 2-25.3 (18, 35, 55), although later studies have questioned this assignment (27,47,67).A number of diffe...