Minireview

Tetraspanins in Viral Infections: a Fundamental Role in Viral Biology?

F. Martin, D. M. Roth, D. A. Jans, C. W. Pouton, L. J. Partridge, P. N. Monk, G. W. Moseley
DOI: 10.1128/JVI.79.17.10839-10851.2005

The tetraspanins are a broadly expressed superfamily of transmembrane glycoproteins with over 30 members found in humans and with homologues conserved through distantly related species, including insects, sponges, and fungi. Members of this family appear to form large integrated signaling complexes or tetraspanin-enriched microdomains (TEMs) by their association with a variety of transmembrane and intracellular signaling/cytoskeletal proteins (49). These interactions link tetraspanins to an array of physiological functions and, in consequence, to numerous endogenous pathologies, including cancer development and inherited disorders (Table 1).

View this table:
TABLE 1.

Members of the tetraspanin superfamily with reported links to pathologiesa

Tetraspanins are also known to have roles in the pathology of infectious diseases such as diphtheria, malaria, and numerous viral infections (Table 1). The literature currently indicates that specific tetraspanin family members are selectively associated with specific viruses and affect multiple stages of infectivity, from initial cellular attachment to syncytium formation and viral particle release. Thus, the relationship of tetraspanins with viruses appears to be particularly complex.

Here, we will consider this data in the context of recent developments in tetraspanin biology, particularly in our understanding of the architecture and function of TEMs. With the benefit of recent insights into tetraspanin function in cell fusion events and intracellular trafficking, we discuss common features of tetraspanin/viral associations which indicate a fundamental role for TEMs in a number of viral infections. We will also consider the existing therapeutic strategies for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human T-cell lymphotropic virus type 1 (HTLV-1), focusing on the potential therapeutic value of targeting TEMs, using peptide reagents based on tetraspanin extracellular regions.

THE TETRASPANIN SUPERFAMILY

Structural features of the tetraspanin superfamily.Tetraspanins are type III membrane glycoproteins which span the plasma membrane four times, producing two extracellular loops and short intracellular regions (Fig. 1). A defining structural signature of the superfamily is the “tetraspanin fold” of the larger extracellular loop (LEL). In this region, disulfide bonding of four absolutely conserved cysteines forms a subloop structure containing a region which is hypervariable between family members and between species homologues of the same tetraspanin (Fig. 1) (81, 142). The cysteines are present in three variously conserved motifs (CysCysGly, ProXSerCys [where X = any amino acid], and GluGlyCys) (Fig. 1), wherein the flexibility and constraint imparted by the conserved Gly residue in CysCysGly and by Pro in ProXSerCys contribute to subloop formation (68). Many members of the tetraspanin family have one or two additional pairs of Cys residues in the tetraspanin fold region, potentially allowing the formation of complex subloop structures. The region of the LEL outside of this subloop shows greater structural conservation, forming three α-helices which not only form a structural platform to present the tetraspanin fold but may also contribute independently to tetraspanin function (see below) (68, 152).

FIG. 1.
FIG. 1.

The tetraspanin CD81. The primary sequence of CD81 (single-letter amino acid code) is shown schematically in the context of its transmembrane architecture. Key conserved residues in the tetraspanin superfamily include charged transmembrane residues and canonical cysteines which are disulfide bonded to form a functional subloop in the LEL. Sites of potential modification by N-glycans and palmitoylation are shown, and approximate locations of sites of molecular associations (homodimerization/heterodimerization of tetraspanins and primary interaction with nontetraspanin proteins) are highlighted. CD81 lacks classical NXS/T glycosylation sites commonly found in other tetraspanins and a broadly conserved E/Q residue in the fourth transmembrane domain. The four residues which differ between human CD81 LEL and African green monkey (T163, F186, E188, D196) CD81 LEL are shown. PKC, protein kinase C.

Conservation of the canonical LEL Cys, Gly, and other residues, including charged transmembrane amino-acids, distinguishes members of the tetraspanin superfamily proper from other “tetraspan” proteins (168). Modification of tetraspanins includes O- and N-linked glycosylation. N glycosylation sites are largely located in the LEL, and glycosylation has been shown to regulate specific tetraspanin functions (111). N glycosylation is generally assumed to occur at classical AsnX Ser/Thr sites, but the LELs of some tetraspanins, including CD9 and CD81, contain the rarer AsnXCys N-glycosylation motif (138) which, interestingly, incorporates canonical cysteines. Mutation of the only AsnXSer sites in CD9 does not prevent N glycosylation, indicating that the AsnXCys site may be utilized in some cases (G. W. Moseley, L. J. Partridge, and P. N. Monk, unpublished data). Palmitoylation of tetraspanins has also been shown to be functionally significant, as it appears to participate in the formation of heterotetraspanin associations (14) and to regulate association with lipid rafts (see below) (16).

Tetraspanin-enriched microdomains.Tetraspanins affect multiple events in vitro, including cellular signaling, migration, adhesion, fusion, cytoskeletal reorganization, and proliferation, which appear relevant to altered expression patterns seen during cellular activation, differentiation, proliferation, and malignant transformation in vivo (reviewed in references 87 and 168). Tetraspanins are expressed by all mammalian tissues, although the complement of family members expressed is tissue specific (Table 1). It is unsurprising, therefore, that tetraspanin functions have been identified in an array of cell types, including platelets, epithelial/endothelial cells, muscle cells, and photoreceptor cells and cells of the immune, central nervous, and reproductive systems (87, 99). The basis for this broad functionality appears to be the capacity of tetraspanins to form multiple intermolecular interactions with a restricted but varied complement of transmembrane and intracellular molecules (Fig. 2).

FIG. 2.
FIG. 2.

Possible architecture of the tetraspanin web. The principal interactions of TEMs are robust primary interactions which involve direct extracellular tetraspanin-protein interactions. Secondary interactions are less robust and include heterotetraspanin interactions which facilitate indirect interaction of primary tetraspanin complex proteins. Tertiary interactions are the least-robust complexes and are thought to reflect large-scale coalescence of the higher order interactions into large signaling domains. Based on the known structure of the tetraspanin-rich urothelial plaque, this order of interactions is shown as interlinked hexagons (98). Interactions within TEMs include homotypic and heterotypic tetraspanin associations and association with adhesion molecules (integrins [9]), immune cell receptors (e.g., Fc receptors and T-cell receptor (TCR), CD4/CD8, and MHC proteins [103, 167]), growth factors and their receptors (pro-HB-EGF [136], pro-transforming growth factor α [144], and epidermal growth factor receptor [110]), intracellular signaling molecules (protein kinases hck, lyn, and PKC [167, 176] and phosphatidylinositol 4-kinase [172]), and cytoskeletal components (27), as well as members of a novel transmembrane immunoglobulin superfamily (EWI-2, EWI-F) (152).

Tetraspanins have no intrinsic enzymatic activity or typical signaling motifs (with the exception of the recently identified 14-3-3 binding motif in CD81 [20]), so it has been predicted that they act primarily as novel adapter proteins, facilitating the interaction of associated molecules in tetraspanin signaling networks (tetraspanin web [135] or TEMs [49]). The evidence that physical associations of tetraspanins are functionally relevant is compelling. For example, in vitro modulation of tetraspanins on cell adhesion/migration or growth have been shown to be dependent on tetraspanin-associated integrins (76, 93, 143) and progrowth factors (75, 144). Similar observations have been made in vivo in tetraspanin-null animals (167).

Analogies have been drawn between TEMs and lipid rafts. In the latter, protein-protein interactions are facilitated by association with membrane regions enriched for cholesterol and glycosphingolipids (149). In either lipid rafts or TEMs the associated proteins are believed to form large, integrated signaling platforms. Although TEMs and lipid rafts exist as separate entities, they have been shown to interact physically and functionally (17, 27).

Architecture of TEMs.Recent studies assessing the strength/proximity of tetraspanin interactions have indicated that TEMs are constructed from a hierarchy of interactions (Fig. 2) (49, 167). Primary (or high-order) tetraspanin interactions generally appear to be mediated by the LEL region, particularly the subloop and proximal regions, a notable exception being homotypic tetraspanin associations, which are suggested to be mediated by regions of the LEL away from the subloop (Fig. 1) (152). These are the most robust of TEM interactions, being stable in relatively hydrophobic detergents such as Triton X-100 and incorporating significant proportions of the cellular complement of the associated proteins. The fact that they can be stabilized by short covalent chemical cross-linkers indicates that they involve direct extracellular interactions.

Secondary interactions involve the transmembrane and/or intracellular regions (Fig. 1) (10, 14). These interactions are less stable in high-stringency detergents but are maintained in milder conditions (Brij-96, Brij-97) and involve tetraspanin-tetraspanin associations that show some dependency on palmitoylation (14). These interactions are thought to indirectly link primary complexes and thereby facilitate their cross talk.

Tertiary, low-order interactions are stable only in low-stringency detergents (CHAPS, Brij-99). While higher order interactions are isolated as discrete entities, tertiary interactions are large complexes containing multiple tetraspanins and associated molecules. Thus, tertiary interactions are hypothesized to result from the large-scale coalescence of higher order complexes. The study of tertiary interactions is complicated by their poor stability and extensive nature, meaning that the composition of the complexes is less well defined than for higher order associations. The use of low-stringency detergents to isolate these complexes suggests the possibility of nonspecific capture of molecules in insoluble micelles. However, several tertiary interactions appear to be functionally relevant or have been confirmed by different methods, including fluorescence resonance energy transfer (154). Importantly, Claas et al. (18) have demonstrated that tertiary interactions can exist independently of lipid rafts/large detergent-insoluble fractions.

Conceptually, TEMs may form extended structures of primary tetraspanin complexes indirectly connected in large contiguous networks (Fig. 2). However, it is unlikely that TEMs are static structures, and the differing properties of primary interactions compared with those of lower order interactions may relate, at least in part, to a more transitory nature of the lower order interactions, not only to their spatial arrangement. The localization of tetraspanin complexes, subcellularly and in the plane of the membrane, is known to change in response to certain stimuli, as does the molecular composition of isolated complexes (59, 118). The dynamic subcellular localization of tetraspanins has been suggested to relate to roles in trafficking of web-associated molecules or as novel chaperone proteins in integrin maturation (9, 33, 60, 89, 134, 173). Moreover, in B cells the CD81/CD21/CD19 coreceptor complex interacts dynamically with lipid rafts, modulated by palmitoylation of CD81 (16), and regulated association of CD82, lipid rafts, and the cytoskeleton has been reported (27). Cytoskeletal association of TEMs is likely to be involved in their subcellular/membrane distribution. Thus, TEMs, like lipid rafts, are likely to be highly dynamic and regulable structures.

Tetraspanin function in vivo.A major feature of the tetraspanin web hypothesis (135) was that it provided an explanation for the similar functional effects of different members of the superfamily observed in vitro. This hypothesis has received support from studies of tetraspanin-null mice, where similar effects of knockouts of CD151, CD81, CD37, Tssc-6 have been seen in T cells (167) and in the CD9-knockout mouse, where CD81 expression in vitro can compensate for deficiencies in sperm-egg fusion (65). Moreover, tetraspanin-knockout mice are largely healthy, generally displaying only mild phenotypic abnormalities. This is surprising, as quite dramatic in vivo phenotypes result from mutation of the primary partners of some tetraspanins (69, 166). Thus, it appears that there is a certain degree of functional redundancy between tetraspanins.

While single-tetraspanin knockouts display mild phenotypes, phenotypic abnormalities are widespread and are found in T cells, platelets, and keratinocytes of CD151-null mice (77, 166), in the central nervous system, B and T cells, and retinal pigment epithelial cells of CD81-null mice (39, 100, 151), and in gametes, smooth muscle cells, and the peripheral nervous system of CD9-null mice (58, 99, 140). It would appear likely, therefore, that TEMs per se have important roles in the physiology of most, if not all, cell types. The removal of a single tetraspanin shows some redundancy, owing to the extensive nature of TEMs and the expression of close homologues. However, the clear phenotypic abnormalities observed indicate that not all functions of a single tetraspanin can be replicated by their counterparts (as is suggested by the evolutionary conservation of the members of this large family). The production of knockout mice lacking multiple tetraspanins may lead to a delineation of the overlapping and unique functions of evolutionarily close members of the tetraspanin family.

As described above, studies of the structure of TEMs have relied heavily on detergent solubility studies, which are clearly limited and relatively insensitive. Similarly, with the data currently available, the functional/physical relationship of tetraspanin associations remains inferred, as it has not formally been correlated through mutagenesis of tetraspanins. The re-expression of mutated tetraspanins in null mice may therefore permit more intricate and physiologically relevant investigations of the structure and functional architecture of TEMs.

TETRASPANINS IN VIRAL INFECTIONS

Given the broad physiological importance of tetraspanins, it is not surprising that tetraspanins have been commonly identified in cellular disorders (Table 1). There is increasing evidence for the involvement of tetraspanins in infections by various microbes, but they have been most commonly identified as playing a role in viral infections. The remainder of this review will focus on these associations.

FLAVIVIRUSES: HCV AND CD81

Interaction of CD81 and HCV-E2. The most exhaustively documented involvement of a tetraspanin in viral infection is of CD81 in HCV infection. HCV is a small, enveloped RNA virus whose genome encodes a single polyprotein that is processed by viral/cellular proteases into structural and nonstructural proteins. Structural proteins include the envelope glycoproteins E1 and E2, which mediate viral binding and entry into host cells (78).

CD81 was the first protein ligand identified for HCV, specifically for E2 protein. The interaction was identified using a cDNA library from a subclone of a human T-cell lymphoma line with high E2 binding capacity and was confirmed by the demonstration that monoclonal antibodies to CD81-LEL can inhibit the binding of recombinant E2 to Epstein-Barr virus-transformed B cells (122) and that human CD81-LEL specifically binds E2 from HCV-infected plasma. The chimpanzee is the only species other than humans that shows susceptibility to HCV (132), and vaccination with E2 glycoproteins can protect chimps from the virus. The physiological significance of CD81/E2 association was implied by the demonstration that this protection correlated with the ability of sera to block their interaction (122).

The sequence in the LEL essential for binding E2 is contained within residues 164 to 201, a region that forms the epitope for antibody 1D6, which inhibits E2 binding to CD81 (Fig. 1) (50). Inhibition of E2 binding by a small peptide analogue of CD81 LEL has highlighted the role of residues 176 to 189 (30). African green monkey (AGM; Cercopithecus aethiops) CD81 differs from human CD81 LEL by only four residues (Fig. 1), but AGM-CD81 is unable to bind to E2 and AGMs are not susceptible to HCV. Reciprocal mutations of human and AGM CD81 have shown that the key residue in this interaction is CD81 Phe186 (50). The importance of Phe186 was confirmed when tamarin monkey (Saguinus imperator) CD81 was shown to be able to bind to E2 with a higher affinity than human CD81 (1). Phe186 is conserved in tamarin CD81, and mutation of this residue can inhibit E2 binding (97). Mutational analysis has determined that the E2 binding site on CD81 also comprises residues Ile182, Asn184, and Leu162, forming a hydrophobic E2 binding surface of approximately 806 Å2 (31). It has also been suggested that the SEL domain is important during HCV infection, although this appears to relate primarily to its role in promoting surface expression of CD81 by masking an intracellular retention signal (91).

E2 binds to cells of human origin but not to cell lines derived from AGM, rat, and rabbit (36). Thus, the interaction appears to be dependent on human (h)CD81 and not to require other molecules in human cells, as rat cell lines can bind E2 protein when transfected with hCD81. Binding to this particular tetraspanin is also specific, as E2 does not bind to hCD9-, hCD63- or hCD151-transfected rat cells (36).

Based on this evidence, it has been suggested that CD81 may be a cellular receptor for HCV. However, recent data indicates that CD81 is not sufficient for HCV entry, and the relevance of the CD81-HCV E2 association for viral entry remains unclear. One study has reported that binding of HCV to three hepatocyte-derived cell lines was not blocked by anti-CD81 antibody (137). It has also been shown that hepatocarcinoma cells that have lost the expression of CD81 mRNA still show a small but detectable level of HCV binding (120). Tamarins are not susceptible to HCV infection, but tamarin CD81 binds to E2 with great affinity (1), while hCD81 transgenic mice cannot be infected with HCV (91) and certain human liver cell lines are nonpermissive to infection by HCV-HIV pseudotypes despite CD81 expression. Thus, it appears that formation of the CD81-E2 complex does not necessarily confer susceptibility to the virus. It has also been observed that different HCV strains utilize CD81 to different extents (70, 94, 131); E2 subtype 1b, for instance, shows a lower binding affinity to CD81-LEL than E2 subtype 1a. The CD81-LEL Phe186Leu mutation has been shown to abolish the binding of CD81 LEL to soluble E2 strain H but not to strain Con 1, even though this mutation has no effect on the ability of transfected HepG2 cells to support infection by pseudotype viruses expressing either Con 1 or strain H E2 (175). Another study using a more diverse range of HCV glycoproteins revealed that the CD81-LEL Asp196Glu mutation reduced the infectivity of HCV pseudotypes expressing CH35, HJC4, and C6a1 glycoproteins by 70 to 96% (94). These data suggest that all HCV pseudotypes require CD81 for infection of HepG2 cells but that the importance of the interactions between CD81 LEL and HCV glycoproteins differs between viral strains. The available evidence suggests that CD81 represents an important component in HCV cellular receptor activity but that this process is complex and likely to involve multiple receptor complexes. Further research will be required to establish the in vivo relevance of these in vitro observations.

CD81 in viral entry and release.There are other candidate receptors for HCV, namely the scavenger receptor class B type 1 (SR-B1) (139), dendritic cell-specific intracellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) (84, 126), and low-density lipoprotein receptor (LDLR) (170). One study has established a requirement for both CD81 and SR-B1 for binding and infectivity of HCV pseudoviruses, indicating a role for CD81 as a coreceptor in pseudotype infections (8). Similarly, pseudotype infections can be inhibited or enhanced by CD81 silencing or expression, respectively (175), indicating a role for CD81 in viral entry. However, CD81 alone may be insufficient for HCV entry, as the antibody-mediated internalization rate of CD81 is extremely low compared with that of other surface proteins such as CD4 and CD71 (120). Chimeras consisting of CD81 and the cytoplasmic domains of two receptors that frequently undergo endocytosis (LDLR and the transferrin receptor [TfR]) have been constructed (156); both chimeras significantly increase the endocytosis of recombinant HCV-E2 protein, anti-CD81 antibody, and E2-enveloped viral particles from the serum of HCV-infected patients. Expression of the chimeras in the Huh7 hepatoma cell line also resulted in increased viral replication, suggesting that additional factors are required for efficient endocytosis of wild-type CD81/virus complexes. Thus the mechanism of receptor-HCV complex internalization is still poorly understood. Some lines of in vitro evidence indicate the involvement of receptor complexes incorporating CD81, but further research will be required to identify additional receptor components which contribute to efficient endocytosis

As discussed above, TEMs may have a general role in regulating the trafficking of proteins associated with tetraspanins. There is precedent of a pathogenic exploitation of these processes: CD81 has been linked to entry of plasmodium into hepatocytes in the context of a parasitophorus vacuole (147). Thus, it is possible that viral proteins which interact with tetraspanins become incorporated into TEMs, facilitating their transport into or out of the cell. In the absence of human CD81, mammalian cells transfected with HCV E1-E2 cDNA almost completely retain these proteins in the endoplasmic reticulum. However, when cotransfected with hCD81, a small fraction of these proteins pass through the Golgi and are found associated with extracellular exosomes (92). The CD81 Asp196Glu mutation decreases the susceptibility to infection (see above), despite having only a minimal effect on binding of E2. It is possible that this mutation decreases infectivity by altering the intracellular trafficking characteristics of CD81 (50), lending further support to the notion that CD81-E2 interactions are involved in facilitating trafficking of HCV particles within the cell. Thus, CD81 may play a role in facilitating viral glycoprotein translocation into exosomes during viral exit and not exclusively in cell entry.

The possible involvement of CD81 in facilitating vacuole trafficking/fusion/release is consistent with hypothesized roles for other tetraspanins in physiological processes (167, 169) and similar to events described for the role of CD63 in HIV-1 infection (see below). In vitro studies showing that anti-CD81 antibody delayed fusion of a mouse myogenic cell line support a role for CD81 in membrane fusion events (155). Anti-CD9 antibody induced the same effect, suggesting that TEMs containing different tetraspanins may be involved in this event. Further evidence for TEM activity includes the demonstration that antibodies to CD9 or CD81 delayed syncytia formation in a rhabdomyosarcoma cell line (155). CD9 is also involved in sperm-egg fusion (15, 79, 99), and significantly, the impaired fusion seen in CD9-null animals can be compensated in vitro by CD81 expression (65). Also, recent data suggest that soluble LEL domains of both CD9 and CD63 can inhibit concanavalin A-induced fusion of human blood monocytes, suggesting that a range of tetraspanins may be involved in the mechanism of cell fusion (V. Parthasarathy, G. W. Moseley, A. Higginbottom, P. N. Monk, R. C. Read, and L. J. Partridge, unpublished data). Therefore, TEMs containing multiple tetraspanins are involved in membrane fusion events which are likely to relate to roles in viral infection.

Potential roles of CD81 and E2 in modulation of the immune response.Although HCV-infected patients show both cellular and humoral immune responses, over 85% are unable to eliminate the virus. In common with other leukocyte-expressed tetraspanins, CD81 has roles in modulating immune cell function (17, 28, 86). An intriguing possibility is that the interaction of CD81 with E2 could modify immune responses in HCV-infected individuals. It has been shown that cross-linking of natural killer (NK) CD81 with immobilized E2 inhibits NK cell response to interleukins-2, -12 and -15, which may affect early innate immune response to HCV infections (21, 159), while E2 cross-linking of CD81 on B- and T-cell lines alters proliferation and aggregation (36). E2 engagement of CD81 also causes the secretion of the chemokine RANTES by CD8+ T cells and the subsequent down-regulation of its receptor, CCR5, a mechanism by which HCV might interfere with lymphocyte migration (109). These events may provide strategies for immune evasion or, alternatively, may relate to the immune dysregulation effects of chronic HCV infections, including type 2 diabetes mellitus, glomerulonephritis, arthritis, and non-Hodgkin's lymphoma (157). As CD81 is widely expressed and involved in an array of functions, there are a number of potential biological effects of E2-CD81 interaction. Flint et al. (36) hypothesized that interactions between E2 on infected hepatocytes and CD81 on uninfected cells could prime the latter for infection. These are certainly intriguing possibilities, and the genuine physiological significance of the biological effects of E2 interactions with CD81 awaits further research.

RETROVIRUSES: HTLV-1, HIV, AND FIV

HTLV-1.HTLV-1 is a type C retrovirus that infects CD4+ lymphocytes in vivo (130), although CD8 T cells may also serve as a reservoir (107). This tropism contrasts with the in vitro ability of viral Env protein to bind and enter multiple cell types (13, 45, 67, 153, 158). The receptor for HTLV-1 is unknown, but a likely candidate is the human GLUT1 glucose transporter (88). Molecules involved in syncytium formation, virus adsorption, and infection include ICAM-1, ICAM-3, VCAM-1, and tetraspanins (22, 52, 123, 124). Cell-cell fusion via syncytium formation is thought to be one of the main transmission mechanisms of HTLV-1 (19). The tetraspanin CD82 was identified as an antigen recognized by several antibodies found to inhibit HTLV-1-mediated syncytium formation (38, 57). Coexpression of CD82 with HTLV-1 Env glycoprotein in COS-1 cells had an inhibitory effect on syncytium formation and HTLV-1 infectivity, although the incorporation of Env into nascent virions was unaffected (124).

CD82 is expressed on the surfaces of most types of peripheral blood mononuclear cells (PBMCs) and granulocytes, although CD16+ NK cells show very low levels of expression and CD4+ T cells express higher levels than CD8+ T cells (57). CD82 is heterogeneously glycosylated in T cells, with apparent molecular mass ranging from 35 to 50 kDa (57). Activation of T cells (e.g., using phytohemagglutinin) and/or infection with HTLV-1 results in up-regulation of CD82 expression and also increases the amount of glycosylation (38, 57). The glycosylation state of CD82 has been shown to be essential for its correct functioning (111, 112), possibly by altering the affinity of CD82 for membrane proteins such as integrins. Coimmunoprecipitation experiments show that HTLV-1 Env glycoproteins interact with highly glycosylated forms of CD82, although interactions with immature forms of the tetraspanin suggest that these interactions occur early in the secretory pathway (124). The tetraspanin CD151 has also been shown to be up-regulated in HTLV-1-infected cells (47, 48), and this has been linked to increased adhesion of infected cells to the extracellular matrix. CD82 also appears to be involved in cellular adhesion and motility events (112), and it is possible that CD151 and CD82 have common functions during HTLV-1 infection. CD82 has recently been proposed to act as an adaptor protein, linking lipid rafts and the actin cytoskeleton in T cells (26). In this role, it is likely to control the function of molecules such as ICAM-1 and β1 integrins that are directly involved in the cell-cell interactions that lead to syncytium formation (22). Thus, although CD82 does not act as a cellular receptor for HTLV-1 or affect expression levels of HTLV-1 proteins, it is likely to function in concert with CD151 and other tetraspanins in TEM-dependent cell fusion events.

HIV-1.Entry of the retrovirus HIV (genus, Lentivirus) into cells occurs in three distinct steps: the attachment of virions to cell surface CD4+ by envelope gp120 protein, the subsequent interplay of the conformationally altered gp120 with cellular CCR5 and CXR4 coreceptors, and, finally, envelope gp41 protein-mediated fusion to target cells (102). The HIV genome consists of two copies of RNA which are reverse transcribed to DNA to form the preintegration complex containing the viral matrix (MA), integrase, and Vpr proteins as well as several host proteins, which is imported into the nucleus and incorporated into the host chromosomes, where it can become latent for 3 to 10 years (44). The subtypes of HIV, HIV-1 and HIV-2, have the same modes of transmission and are associated with similar opportunistic infections, but immunodeficiency seems to develop more slowly with HIV-2 (90, 148).

A role for the tetraspanin CD63 in HIV-1 infection was first suggested when it was shown to be up-regulated from intracellular vesicles to the surfaces of HIV-1-infected cells and selectively incorporated into budding structures and newly synthesized virus particles (95, 96). Consistent with a role in viral release, vesicle fractions in infected H9 T cells contain increased levels of CD63 compared with noninfected cells (41).

Macrophages are sources of virus reservoirs during HIV-1 infection: previous work has described organelles within macrophages as preferential sites for virus accumulation in macrophages (114). Expression analysis revealed high levels of CD63 and major histocompatibility complex type II (MHC II) and low levels of Lamp 1 in these organelles, resembling the compartments where MHC II molecules undergo the final stages of maturation. CD63 is also enriched on the surface of multivesicular bodies, and it is presumed that HIV-1 particles mimic the mechanisms utilized in the production of natural internal vesicles (128). Thus it is possible that CD63, like CD81 and CD82 (see above), may be involved in viral trafficking and/or association with intracellular vesicles for fusion and release.

It has recently been shown that HIV-1 infection is inhibited by anti-CD63 antibodies, but not by antibodies to CD9 or CD81. This was specific for macrophages and HIV-1 strains which use the CCR5 coreceptor, as X4 virus and T-cell infection were unaffected by anti-CD63 antibodies (161). Preliminary data also shows that recombinant tetraspanin-LEL proteins can also specifically inhibit macrophage infection but, in contrast to antibody inhibitors, can also inhibit CXCR4-tropic virus; significantly, the effect is seen with a range of tetraspanin-LELs (including CD9 and CD81) (S. H. Ho, F. Martin, G. W. Moseley, L. J. Partridge, C. Cheng-Mayer, and P. N. Monk, unpublished data). These experiments indicate a role for multiple tetraspanins, probably organized in TEMs, in the infection of macrophages by HIV. The differences observed between the studies using tetraspanin LELs and antibodies may be due to a number of factors, as neither approach is physiological. However, tetraspanin LELs are small proteins and are not prone to the same artifacts as antibodies such as Fc receptor coengagement, known to suppress HIV replication in macrophages (119). Alternatively, the differing efficacy of antibodies may relate to epitope-specific events, as described for anti-CD82 in syncytium formation (57). It is also possible that anti-CD63 antibodies bind directly to the viral envelope, known to contain higher levels of CD63 than other tetraspanins, thus inhibiting infection by steric hindrance (117). However, the apparent involvement of CD9 and CD81 in HIV-1 infection implies that TEMs are involved in HIV-1 infection and that this role may involve vacuolar targeting and membrane fusion events in viral release.

FIV.Feline immunodeficiency virus (FIV) infection also appears to involve tetraspanins, in this case CD9 (164). In 104-C1 PBMC cells transfected to express feline (f)CD9, the anti-CD9 antibody vpg15 was shown to delay reversibly, but not completely block, reverse transcriptase activity following infection (29). As the inhibitory effect was enhanced upon addition of antibody postinfection, it appeared that CD9 can affect events after cellular entry. Treatment of chronically infected cells with vpg15 reduced the numbers of budding particles at the plasma membrane and inhibited FIV spread in cell culture, so it appears likely that viral assembly and/or release (29) is inhibited by anti-CD9 antibody, indicating a role for fCD9 similar to that of other tetraspanins in viral infections. FIV can infect CD9-negative 3201 cells (55), implying that CD9 is not essential for FIV infection or at least that other tetraspanins can take over this role. However, ectopic expression of CD9 in 3201 cells enhances FIV infectivity, suggesting that CD9 plays a direct role in infection rather than an indirect role via cell signaling pathways affected by anti-CD9 antibody ligation (163).

PARAMYXOVIRUS

Canine distemper virus (CDV) (a morbillivirus of the Paramyxoviridae family) is a negative-stranded RNA virus, similar to human measles virus, for which the host cell surface receptor(s) are currently not identified (46). As for FIV, an anti-CD9 antibody has been shown to inhibit viral infection (83) and transfection of CD9 into cell lines increases viral production, leading to a greater number of infectious centers and larger syncytia, consistent with the effects of CD9 expression on syncytium formation by a rhabdomyosarcoma cell line (155). CD9 does not appear to be a receptor for CDV (83), and anti-CD9 antibody does not block CDV attachment to cells (141). The involvement in subsequent events (83), including membrane fusion/syncytium formation, is comparable to that of other tetraspanins in human viral diseases and CD9 in FIV.

TETRASPANINS AS POTENTIAL THERAPEUTIC TARGETS FOR VIRUSES THAT INFECT HUMANS

HCV infects 170 million people worldwide, causing liver diseases that include hepatitis, cirrhosis, hepatocellular carcinoma, and disorders relating to immune dysregulation (125, 157). HIV/AIDS is responsible for more than 25 million deaths since 1984, with an estimated 37.8 million individuals currently infected (Joint United Nations Program on HIV/AIDS, UNAIDS, 2004). HTLV-1 presently infects 20 million individuals worldwide (32) and is associated with adult T-cell-leukemia/lymphoma and myelopathy/tropical spatic paraparesis. Treatments for these viruses include antiviral drugs such as interferons, viral enzyme inhibitors, and viral-cell receptor interaction inhibitors (24, 25, 35, 62, 71, 100, 157), which can substantially lower the viral load (115) but cannot eliminate the virus. Further problems associated with such treatments include toxicity and side effects, high cost, development of viral resistance, and low efficacy owing to viral genotype specificity/patient variables (11, 43, 61, 101, 108, 121, 145, 157, 171). Efforts to develop conventional vaccines for HIV have been hampered by potential pathogenicity and poor capacity to elicit protective immune responses (6, 54, 80, 162). Several new vaccination approaches for HIV (e.g., DNA and viral vectors) are in clinical trials (3, 4, 7, 23, 82, 105, 133, 146). However, in common with conventional vaccines, most of these strategies have been shown to be ineffective due either to their poor capacity to elicit immune protection (40, 85) or to the various mechanisms of HIV immune evasion, such as high rate of mutations and host genome insertion (34, 53, 72, 73, 106, 116, 127).

As described above, various groups have identified tetraspanins as the targets of antibodies which inhibit the infectivity of a range of viruses but have generally identified a specific tetraspanin in each of these studies. However, it appears that at least two tetraspanins may be involved in HTLV-1 infection and at least four in HIV-1 infection. Thus, we hypothesize that (i) several tetraspanins will be involved in some or all of the viral life cycles here mentioned, and (ii) that tetraspanins are likely to be involved in many other viral infections as yet undiscovered. While definition of the precise roles of TEMs in viral infection awaits further research, it has already been shown that peptides based on tetraspanin-LELs can inhibit tetraspanin functions such as sperm/oocyte fusion (51). A peptide inhibitor of only 14 residues, designed to mimic the region 176 to 189 of CD81 has been shown to inhibit the CD81-E2 interaction (30). With a greater understanding of the association of TEMs with viral proteins, particularly the primary ligand interactions, it should become possible to selectively target TEMs for therapy. The E2 binding site on CD81 has been mapped to specific amino acids in the LEL subloop (31, 160). Based on these findings, several bi-imidazole-based compounds that can also inhibit E2 binding to CD81 have been identified (160). These resemble the solvent-exposed face of the helix of CD81 LEL that contains Phe186, thus mimicking the E2 binding site on CD81. Two of the compounds have 50% inhibitory concentration values below 100 μM and represent an important proof of the concept that tetraspanin-based drugs can disrupt biological function. Thus, targeting TEMs may provide a novel strategy to inhibit critical processes of viral infection.

CONCLUDING REMARKS

The precise nature of the relationship of tetraspanins with viruses is presently poorly defined and is complicated by the apparently disparate functions of specific tetraspanins in infections by different viruses (summarized in Fig. 3). However, much of the data describing this relationship has been derived from in vitro studies. Thus, it is unclear whether modulation of immune cell line function by LEL-CD81 ligation, for example, has any genuine significance in vivo. Similarly, while CD81 is known to interact with HCV coat proteins in vitro, the stage of infection at which this interaction occurs in vivo is unknown and need not necessarily occur during cell entry. Indeed the interaction of CD82 with HTLV-1 proteins occurs postinfection, while CD9 and CD63 appear to affect FIV/CDV and HIV-1 late in infection. Of particular significance is the recent demonstration that soluble LEL proteins from several different tetraspanins can inhibit HIV-1 infection and the overlapping effects of certain antitetraspanin antibodies in syncytium formation by rhabdomyosarcoma cells. This suggests that there is functional overlap between different tetraspanins involved in viral infection processes, which implies the involvement of TEMs.

FIG. 3.
FIG. 3.

Model for the role of TEMs in viral infection. Current evidence (represented in inset) indicates that viral proteins may associate with TEMs by forming direct primary interactions with a tetraspanin (black arrows) which, via secondary/tertiary interactions of tetraspanins (grey arrow), incorporate the viral protein into the tetraspanin web, permitting indirect interaction with tetraspanin-associated molecules (dotted arrow). Various data indicate that, through these interactions, TEMs may be involved in initial viral attachment (no. 1) and entry (no. 2) into the cell. Some data also indicate that viral interaction with TEMs may couple to intracellular signaling pathways, priming cells for infection or altering immune cell functions (no. 3). TEMs may interact with new viral proteins after infection/transcription in the biosynthesis/secretion pathway (no. 4). Multiple lines of evidence also indicate that TEM involvement in membrane fusion events may be exploited for viral exit from cells whether via direct release by secretory vesicles or in exosomes (no. 5 and 6) or via cell-cell fusion to form syncytia (no. 7). In the latter, tetraspanin-associated cell adhesion molecules (e.g., ICAM, integrins) are likely to mediate intercellular interactions in the fusion process.

Thus, rather than being passive targets for opportunistic viral attachment to cells, tetraspanins are likely to play a more fundamental role in viral infectivity through the involvement of TEMs in viral protein maturation/trafficking, in cell-cell fusion events or in other membrane fusion events involved in viral release, processes which have clear parallels in normal TEM physiology. In this context, the selective primary interaction of viral protein with a specific tetraspanin (e.g., CD81 with HCV E2) to connect it via secondary/tertiary interactions to tetraspanin complexes involved in these processes would be typical of the incorporation of nontetraspanin proteins into the TEMs (Fig. 3). Targeting TEMs for viral therapies may therefore target a principal mechanism in the infectious cycles of HIV-1, HTLV-1, and HCV which viral mutation would not readily circumvent, providing new antiviral therapies so urgently required by an ever-increasing percentage of the world's population.

REFERENCES

  1. 1.↵
    Allander, T., X. Forns, S. U. Emerson, R. H. Purcell, and J. Bukh. 2000. Hepatitis C virus envelope protein E2 binds to CD81 of tamarins. Virology277:358-367.
    OpenUrlCrossRefPubMed
  2. 2.
    Reference deleted.
  3. 3.↵
    Amara, R. R., F. Villinger, J. D. Altman, S. L. Lydy, S. P. O'Neil, S. I. Staprans, D. C. Montefiori, Y. Xu, J. G. Herndon, L. S. Wyatt, M. A. Candido, N. L. Kozyr, P. L. Earl, J. M. Smith, H. L. Ma, B. D. Grimm, M. L. Hulsey, J. Miller, H. M. McClure, J. M. McNicholl, B. Moss, and H. L. Robinson. 2001. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science292:69-74.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    Andino, R., D. Silvera, S. D. Suggett, P. L. Achacoso, C. J. Miller, D. Baltimore, and M. B. Feinberg. 1994. Engineering poliovirus as a vaccine vector for the expression of diverse antigens. Science265:1448-1451.
    OpenUrlAbstract/FREE Full Text
  5. 5.
    Ashman, L., S. Fitter, P. M. Sincock, L. Nguyen, and A. C. Cambareri. 1997. CD151 (PETA-3) workshop summary report, p. 681-683. In T. Kishimoto et al. (ed.), Leukocyte typing VI. Garland Publishing, New York, N.Y.
  6. 6.↵
    Baba, T. W., Y. S. Jeong, D. Pennick, R. Bronson, M. F. Greene, and R. M. Ruprecht. 1995. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science267:1820-1825.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    Barouch, D. H., S. Santra, M. J. Kuroda, J. E. Schmitz, R. Plishka, A. Buckler-White, A. E. Gaitan, R. Zin, J. H. Nam, L. S. Wyatt, M. A. Lifton, C. E. Nickerson, B. Moss, D. C. Montefiori, V. M. Hirsch, and N. L. Letvin. 2001. Reduction of simian-human immunodeficiency virus 89.6P viremia in rhesus monkeys by recombinant modified vaccinia virus Ankara vaccination. J. Virol.75:5151-5158.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    Bartosch, B., A. Vitelli, C. Granier, C. Goujon, J. Dubuisson, S. Pascale, E. Scarselli, R. Cortese, A. Nicosia, and F. L. Cosset. 2003. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J. Biol. Chem.278:41624-41630.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    Berditchevski, F. 2001. Complexes of tetraspanins with integrins: more than meets the eye. J. Cell Sci.114:4143-4151.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    Berditchevski, F., E. Gilbert, M. R. Griffiths, S. Fitter, L. Ashman, and S. J. Jenner. 2001. Analysis of the CD151-α3β1 integrin and CD151-tetraspanin interactions by mutagenesis. J. Biol. Chem.276:41165-41174.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    Besson, C., Y. Plumelle, B. Arnulf, C. Gonin, G. Panelatti, A. Bazarbachi, and O. Hermine. 2001. Adult T-cell leukemia/lymphoma. Therapeutic aspects. Presse Med.30:243-245. (In French.)
    OpenUrlPubMed
  12. 12.
    Boucheix, C., G. H. Duc, C. Jasmin, and E. Rubinstein. 2001. Tetraspanins and malignancy. Expert Rev. Mol. Med.31:1-17.
    OpenUrl
  13. 13.↵
    Cavrois, M., A. Gessain, S. Wain-Hobson, and E. Wattel. 1996. Proliferation of HTLV-1 infected circulating cells in vivo in all asymptomatic carriers and patients with TSP/HAM. Oncogene12:2419-2423.
    OpenUrlPubMedWeb of Science
  14. 14.↵
    Charrin, S., S. Manie, M. Oualid, M. Billard, C. Boucheix, and E. Rubinstein. 2002. Differential stability of tetraspanin/tetraspanin interactions: role of palmitoylation. FEBS Lett.516:139-144.
    OpenUrlCrossRefPubMedWeb of Science
  15. 15.↵
    Chen, M. S., K. S. Tung, S. A. Coonrod, Y. Takahashi, D. Bigler, A. Chang, Y. Yamashita, P. W. Kincade, J. C. Herr, and J. M. White. 1999. Role of the integrin-associated protein CD9 in binding between sperm ADAM 2 and the egg integrin α6β1: implications for murine fertilization. Proc. Natl. Acad. Sci. USA96:11830-11835.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    Cherukuri, A., R. H. Carter, S. Brooks, W. Bornmann, R. Finn, C. S. Dowd, and S. K. Pierce. 2004. B cell signaling is regulated by induced palmitoylation of CD81. J. Biol. Chem.279:31973-31982.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    Cherukuri, A., T. Shoham, H. W. Sohn, S. Levy, S. Brooks, R. Carter, and S. K. Pierce. 2004. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J. Immunol.172:270-280.
    OpenUrl
  18. 18.↵
    Claas, C., C. S. Stipp, and M. E. Hemler. 2001. Evaluation of prototype transmembrane 4 superfamily protein complexes and their relation to lipid rafts. J. Biol. Chem.276:7974-7984.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    Clapham, P., K. Nagy, R. Cheingsong-Popov, M. Exley, and R. A. Weiss. 1983. Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line. Science222:1125-1127.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    Clark, K., A. Oelke, M. E. Johnson, K. D. Eilert, P. C. Simpson, and S. C. Todd. 2004. CD81 associates with 14-3-3 in a redox-regulated palmitoylation-dependent manner. J. Biol. Chem.279:19401-19406.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    Crotta, S., A. Stilla, A. Wack, A. D'Andrea, S. Nuti, U. D'Oro, M. Mosca, F. Filliponi, R. M. Brunetto, F. Bonino, S. Abrignani, and N. M. Valiante. 2002. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J. Exp. Med.195:35-41.
    OpenUrlCrossRefPubMedWeb of Science
  22. 22.↵
    Daenke, S., S. A. McCracken, and S. Booth. 1999. Human T-cell leukaemia/lymphoma virus type 1 syncytium formation is regulated in a cell-specific manner by ICAM-1, ICAM-3 and VCAM-1 and can be inhibited by antibodies to integrin beta2 or beta7. J. Gen. Virol.80:1429-1436.
    OpenUrlCrossRefPubMedWeb of Science
  23. 23.↵
    Davis, N. L., I. J. Caley, K. W. Brown, M. R. Betts, D. M. Irlbeck, K. M. McGrath, M. J. Connell, D. C. Montefiori, J. A. Frelinger, R. Swanstrom, P. R. Johnson, and R. E. Johnston. 2000. Vaccination of macaques against pathogenic simian immunodeficiency virus with Venezuelan equine encephalitis virus replicon particles. J. Virol.74:371-378.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    Dean, M., M. Carrington, C. Winkler, G. A. Huttley, M. W. Smith, R. Allikmets, J. J. Goedert, S. P. Buchbinder, E. Vittinghoff, E. Gomperts, S. Donfield, D. Vlahov, R. Kaslow, A. Saah, C. Rinaldo, R. Detels, and S. J. O'Brien. 1996. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science273:1856-1862.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    De Clercq, E. 2004. Antiviral drugs in current clinical use. J. Clin. Virol.30:115-133.
    OpenUrlCrossRefPubMedWeb of Science
  26. 26.↵
    Delaguillaumie, A., J. Harriague, S. Kohanna, G. Bismuth, E. Rubinstein, M. Seigneuret, and H. Conjeaud. 2004. Tetraspanin CD82 controls the association of cholesterol-dependent microdomains with the actin cytoskeleton in T lymphocytes: relevance to co-stimulation. J. Cell Sci.117:5269-5282.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    Delaguillaumie, A., Harriague, J., Kohanna, S., Bismuth, G., Rubinstein, E., Seigneuret, M., Conjeaud, H. 2004. Tetraspanin CD82 controls the association of cholesterol-dependent microdomains with the actin cytoskeleton in T lymphocytes: relevance to co-stimulation. J. Cell Sci.117:5269-5282.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    Deng, J., R. H. Dekruyff, G. J. Freeman, D. T. Umetsu, and S. Levy. 2002. Critical role of CD81 in cognate T-B cell interactions leading to Th2 responses. Int. Immunol.14:513-523.
    OpenUrlCrossRefPubMedWeb of Science
  29. 29.↵
    de Parseval, A., D. L. Lerner, P. Borrow, B. J. Willett, and J. H. Elder. 1997. Blocking of feline immunodeficiency virus infection by a monoclonal antibody to CD9 is via inhibition of virus release rather than interference with receptor binding. J. Virol.71:5742-5749.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    Dhanasekaran, M., P. W. Baures, S. VanCompernolle, S. Todd, and O. Prakash. 2003. Structural characterization of peptide fragments from hCD81-LEL. J. Pept. Res.61:80-89.
    OpenUrlCrossRefPubMed
  31. 31.↵
    Drummer, H. E., K. A. Wilson, and P. Poumbourios. 2002. Identification of the hepatitis C virus E2 glycoprotein binding site on the large extracellular loop of CD81. J. Virol.76:11143-11147.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    Edlich, R. F., J. A. Arnette, and F. M. Williams. 2000. Global epidemic of human T-cell lymphotropic virus type-I (HTLV-I). J. Emerg. Med.18:109-119.
    OpenUrlCrossRefPubMedWeb of Science
  33. 33.↵
    Engering, A., and J. Pieters. 2001. Association of distinct tetraspanins with MHC class II molecules at different subcellular locations in human immature dendritic cells. Int. Immunol.13:1713-1723.
    OpenUrl
  34. 34.↵
    Finzi, D., and R. F. Siliciano. 1998. Viral dynamics in HIV-1 infection. Cell93:665-671.
    OpenUrlCrossRefPubMedWeb of Science
  35. 35.↵
    Flexner, C. 1998. HIV-protease inhibitors. N. Engl. J. Med.338:1281-1292.
    OpenUrlCrossRefPubMedWeb of Science
  36. 36.↵
    Flint, M., C. Maidens, L. D. Loomis-Price, C. Shotton, J. Dubuisson, P. Monk, A. Higginbottom, S. Levy, and J. A. McKeating. 1999. Characterization of hepatitis C virus E2 glycoprotein interaction with a putative cellular receptor, CD81. J. Virol.73:6235-6244. 37. Reference deleted.
    OpenUrlAbstract/FREE Full Text
  37. 37.
    Reference deleted.
  38. 38.↵
    Fukudome, K., M. Furuse, T. Imai, M. Nishimura, S. Takagi, Y. Hinuma, and O. Yoshie. 1992. Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV-1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive T cells. J. Virol.66:1394-1401.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    Geisert, E. J., R. W. Williams, G. R. Geisert, L. Fan, A. M. Asbury, H. T. Maecker, J. Deng, and S. Levy. 2002. Increased brain size and glial cell number in CD81-null mice. J. Comp. Neurol.453:22-32.
    OpenUrlCrossRefPubMedWeb of Science
  40. 40.↵
    Giri, M., K. E. Ugen, and D. B. Weiner. 2004. DNA vaccines against human immunodeficiency virus type 1 in the past decade. Clin. Microbiol. Rev.17:370-389.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    Gluschankof, P., I. Mondor, H. R. Gelderblom, and Q. J. Sattentau. 1997. Cell membrane vesicles are a major contaminant of gradient-enriched human immunodeficiency virus type-1 preparations. Virology230:125-133.
    OpenUrlCrossRefPubMedWeb of Science
  42. 42.
    Goldberg, A., and R. S. Molday. 1996. Defective subunit assembly underlies a digenic form of retinitis pigmentosa linked to mutations in peripherin/rds and rom-1. Proc. Natl. Acad. Sci. USA26:13726-13730.
    OpenUrl
  43. 43.↵
    Gout, O., A. Gessain, M. Iba-Zizen, S. Kouzan, F. Bolgert, G. de The, and O. Lyon-Caen. 1991. The effect of zidovudine on chronic myelopathy associated with HTLV-1. J. Neurol.238:108-109.
    OpenUrlCrossRefPubMedWeb of Science
  44. 44.↵
    Greene, W. C. 2004. The brightening future of HIV therapeutics. Nat. Immunol.5:867-871.
    OpenUrlCrossRefPubMed
  45. 45.↵
    Hanon, E., J. C. Stinchcombe, M. Saito, B. E. Asquith, G. P. Taylor, Y. Tanaka, J. N. Weber, G. M. Griffiths, and C. R. Bangham. 2000. Fratricide among CD8+ T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity13:657-664.
    OpenUrlCrossRefPubMedWeb of Science
  46. 46.↵
    Harder, T. C., and A. D. Osterhaus. 1997. Canine distemper virus[em]a morbillivirus in search of new hosts? Trends Microbiol.5:120-124.
    OpenUrlCrossRefPubMedWeb of Science
  47. 47.↵
    Hasegawa, H., T. Nomura, K. Kishimoto, K. Yanagisawa, and S. Fujita. 1998. SFA-1/PETA-3 (CD151), a member of the transmembrane 4 superfamily, associates preferentially with α5β1 integrin and regulates adhesion of human T cell leukemia virus type 1-infected T cells to fibronectin. J. Immunol.161:3087-3095.
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    Hasegawa, H., Y. Utsunomiya, K. Kishimoto, K. Yanagisawa, and S. Fujita. 1996. SFA-1, a novel cellular gene induced by human T-cell leukemia virus type 1, is a member of the transmembrane 4 superfamily. J. Virol.70:3258-3263.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    Hemler, M. 2003. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu. Rev. Cell Dev. Biol.19:397-422.
    OpenUrlCrossRefPubMedWeb of Science
  50. 50.↵
    Higginbottom, A., E. R. Quinn, C. C. Kuo, M. Flint, L. H. Wilson, E. Bianchi, A. Nicosia, P. N. Monk, J. A. McKeating, and S. Levy. 2000. Identification of amino acid residues in CD81 critical for interaction with hepatitis C virus envelope glycoprotein E2. J. Virol.74:3642-3649.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    Higginbottom, A., Y. Takahashi, L. Bolling, S. A. Coonrod, J. M. White, L. J. Partridge, and P. N. Monk. 2003. Structural requirements for the inhibitory action of the CD9 large extracellular domain in sperm/oocyte binding and fusion. Biochem. Biophys. Res. Commun.311:208-214.
    OpenUrlCrossRefPubMedWeb of Science
  52. 52.↵
    Hildreth, J. E., A. Subramanium, and R. A. Hampton. 1997. Human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation mediated by vascular cell adhesion molecule-1: evidence for involvement of cell adhesion molecules in HTLV-1 biology. J. Virol.71:1173-1180.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    Ho, D. D., A. U. Neumann, A. S. Perelson, W. Chen, J. M. Leonard, and M. Markowitz. 1995. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature373:123-126.
    OpenUrlCrossRefPubMedWeb of Science
  54. 54.↵
    Hofmann-Lehmann, R., J. Vlasak, A. L. Williams, A. L. Chenine, H. M. McClure, D. C. Anderson, S. O'Neil, and R. M. Ruprecht. 2003. Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation. AIDS17:157-166.
    OpenUrlCrossRefPubMedWeb of Science
  55. 55.↵
    Hohdatsu, T., H. Hirabayashi, K. Motokawa, and H. Koyama. 1996. Comparative study of the cell tropism of feline immunodeficiency virus isolates of subtypes A, B and D classified on the basis of the env gene V3-V5 sequence. J. Gen. Virol.77:93-100.
    OpenUrlPubMedWeb of Science
  56. 56.
    Huerta, S., D. M. Harris, A. Jazirehi, B. Bonavida, D. Elashoff, E. H. Livingston, and D. Heber. 2003. Gene expression profile of metastatic colon cancer cells resistant to cisplatin-induced apoptosis. Int. J. Oncol.22:663-670.
    OpenUrlPubMed
  57. 57.↵
    Imai, T., K. Fukudome, S. Takagi, M. Nagira, M. Furuse, N. Fukuhara, M. Nishimura, Y. Hinuma, and O. Yoshie. 1992. C33 antigen recognized by monoclonal antibodies inhibitory to human T cell leukemia virus type 1-induced syncytium formation is a member of a new family of transmembrane proteins including CD9, CD37, CD53, and CD63. J. Immunol.149:2879-2886.
    OpenUrlAbstract
  58. 58.↵
    Ishibashi, T., L. Ding, K. Ikenaka, Y. Inoue, K. Miyado, E. Mekada, and H. Baba. 2004. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J. Neurosci.24:96-102.
    OpenUrlAbstract/FREE Full Text
  59. 59.↵
    Israels, S., E. M. McMillan-Ward, J. Easton, C. Robertson, and A. McNicol. 2001. CD63 associates with the alphaIIb beta3 integrin-CD9 complex on the surface of activated platelets. Thromb. Haemostasis85:134-141.
    OpenUrlPubMedWeb of Science
  60. 60.↵
    Ivaska, J., R. D. Whelan, R. Watson, P. J. Parker. 2002. PKC epsilon controls the traffic of beta1 integrins in motile cells. EMBO J.21:3608-3619.
    OpenUrlAbstract
  61. 61.↵
    Izumo, S., I. Goto, Y. Itoyama, T. Okajima, S. Watanabe, Y. Kuroda, S. Araki, M. Mori, S. Nagataki, S. Matsukura, T. Akamine, M. Nakagawa, I. Yamamoto, and M. Osame. 1996. Interferon-alpha is effective in HTLV-I-associated myelopathy: a multicenter, randomized, double-blind, controlled trial. Neurology46:1016-1021.
    OpenUrlAbstract/FREE Full Text
  62. 62.↵
    Jacobson, J. M., R. J. Israel, I. Lowy, N. A. Ostrow, L. S. Vassilatos, M. Barish, D. N. Tran, B. M. Sullivan, T. J. Ketas, T. J. O'Neill, K. A. Nagashima, W. Huang, C. J. Petropoulos, J. P. Moore, P. J. Maddon, and W. C. Olson. 2004. Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542. Antimicrob. Agents Chemother.48:423-429.
    OpenUrlAbstract/FREE Full Text
  63. 63.
    Jankowski, S. A., D. S. Mitchell, S. H. Smith, J. M. Trent, and P. S. Meltzer. 1994. SAS, a gene amplified in human sarcomas, encodes a new member of the transmembrane 4 superfamily of proteins. Oncogene9:1205-1211.
    OpenUrlPubMedWeb of Science
  64. 64.
    Jones, M., and D. Y. Mason. 1997. CD81 workshop panel report, p. 187-188. In T. Kishimoto et al. (ed.), Leukocyte typing VI. Garland Publishing, New York, N.Y.
  65. 65.↵
    Kaji, K., S. Oda, S. Miyazaki, and A. Kudo. 2002. Infertility of CD9-deficient mouse eggs is reversed by mouse CD9, human CD9, or mouse CD81; polyadenylated mRNA injection developed for molecular analysis of sperm-egg fusion. Dev. Biol.247:327-334. 66. Reference deleted.
    OpenUrlCrossRefPubMedWeb of Science
  66. 66.
    Reference deleted.
  67. 67.↵
    Kim, F. J., N. Manel, Y. Boublik, J. L. Battini, and M. Sitbon. 2003. Human T-cell leukemia virus type 1 envelope-mediated syncytium formation can be activated in resistant mammalian cell lines by a carboxy-terminal truncation of the envelope cytoplasmic domain. J. Virol.77:963-969.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    Kitadokoro, K., D. Bordo, G. Galli, R. Petracca, F. Falugi, S. Abrignani, G. Grandi, and M. Bolognesi. 2001. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J.20:12-18.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    Kreidberg, J., M. J. Donovan, S. L. Goldstein, H. Rennke, K. Shepherd, R. C. Jones, and R. Jaenisch. 1996. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development122:3537-3547.
    OpenUrlAbstract
  70. 70.↵
    Kronenberger, B., C. Sarrazin, W. P. Hofmann, M. von Wagner, E. Herrmann, C. Welsch, R. Elez, B. Ruster, A. Piiper, and S. Zeuzem. 2004. Mutations in the putative HCV-E2 CD81 binding regions and correlation with cell surface CD81 expression. J. Viral Hepatol.11:310-318.
    OpenUrlCrossRefPubMedWeb of Science
  71. 71.↵
    Kuritzkes, D. R., J. Jacobson, W. G. Powderly, E. Godofsky, E. DeJesus, F. Haas, K. A. Reimann, J. L. Larson, P. O. Yarbough, V. Curt, and W. R. Shanahan, Jr. 2004. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J. Infect. Dis.189:286-291.
    OpenUrlCrossRefPubMedWeb of Science
  72. 72.↵
    Kwong, P. D., M. L. Doyle, D. J. Casper, C. Cicala, S. A. Leavitt, S. Majeed, T. D. Steenbeke, M. Venturi, I. Chaiken, M. Fung, H. Katinger, P. W. Parren, J. Robinson, D. Van Ryk, L. Wang, D. R. Burton, E. Freire, R. Wyatt, J. Sodroski, W. A. Hendrickson, and J. Arthos. 2002. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature420:678-682.
    OpenUrlCrossRefPubMedWeb of Science
  73. 73.↵
    Kwong, P. D., R. Wyatt, J. Robinson, R. W. Sweet, J. Sodroski, and W. A. Hendrickson. 1998. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature393:648-659.
    OpenUrlCrossRefPubMedWeb of Science
  74. 74.
    Lagaudriere-Gesbert, C., and H. Conjeaud. 1997. CD82 workshop panel report, p. 189-190. In T. Kishimoto (ed.), Leukocyte typing VI. Garland Publishing, New York, N.Y.
  75. 75.↵
    Lagaudriere-Gesbert, C., F. Le Naour, S. Lebel-Binay, M. Billard, E. Lemichez, P. Boquet, C. Boucheix, H. Conjeaud, and E. Rubinstein. 1997. Functional analysis of four tetraspans, CD9, CD53, CD81, and CD82, suggests a common role in costimulation, cell adhesion, and migration: only CD9 upregulates HB-EGF activity. Cell. Immunol.182:105-112.
    OpenUrlCrossRefPubMedWeb of Science
  76. 76.↵
    Lammerding, J., A. R. Kazarov, H. Huang, R. T. Lee, and M. E. Hemler. 2003. Tetraspanin CD151 regulates α6β1 integrin adhesion strengthening. Proc. Natl. Acad. Sci. USA100:7616-7621.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    Lau, L., J. L. Wee, M. D. Wright, G. W. Moseley, P. M. Hogarth, L. K. Ashman, and D. E. Jackson. 2004. The tetraspanin superfamily member CD151 regulates outside-in integrin alphaIIbbeta3 signaling and platelet function. Blood104:2368-2375.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    Lauer, G. M., and B. D. Walker. 2001. Hepatitis C virus infection. N. Engl. J. Med.345:41-52.
    OpenUrlCrossRefPubMedWeb of Science
  79. 79.↵
    Le Naour, F., E. Rubinstein, C. Jasmin, M. Prenant, and C. Boucheix. 2000. Severely reduced female fertility in CD9-deficient mice. Science287:319-321.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    Levine, A. M., S. Groshen, J. Allen, K. M. Munson, D. J. Carlo, A. E. Daigle, F. Ferre, F. C. Jensen, S. P. Richieri, R. J. Trauger, J. W. Parker, P. L. Salk, and J. Salk. 1996. Initial studies on active immunization of HIV-infected subjects using a gp120-depleted HIV-1 immunogen: long-term follow-up. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.11:351-364.
    OpenUrlCrossRefPubMedWeb of Science
  81. 81.↵
    Levy, S., S. C. Todd, and H. T. Maecker. 1998. CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu. Rev. Immunol.16:89-109.
    OpenUrlCrossRefPubMedWeb of Science
  82. 82.↵
    Liu, X. L., K. R. Clark, and P. R. Johnson. 1999. Production of recombinant adeno-associated virus vectors using a packaging cell line and a hybrid recombinant adenovirus. Gene Ther.6:293-299.
    OpenUrlCrossRefPubMedWeb of Science
  83. 83.↵
    Löffler, S., F. Lottspeich, F. Lanza, D. O. Azorsa, V. ter Meulen, and J. Schneider-Schaulies. 1997. CD9, a tetraspan transmembrane protein, renders cells susceptible to canine distemper virus. J. Virol.71:42-49.
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    Lozach, P. Y., H. Lortat-Jacob, A. de Lacroix de Lavalette, I. Staropoli, S. Foung, A. Amara, C. Houles, F. Fieschi, O. Schwartz, J. L. Virelizier, F. Arenzana-Seisdedos, and R. Altmeyer. 2003. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J. Biol. Chem.278:20358-20366.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    Lu, S., J. Arthos, D. C. Montefiori, Y. Yasutomi, K. Manson, F. Mustafa, E. Johnson, J. C. Santoro, J. Wissink, J. I. Mullins, J. R. Haynes, N. L. Letvin, M. Wyand, and H. L. Robinson. 1996. Simian immunodeficiency virus DNA vaccine trial in macaques. J. Virol.70:3978-3991.
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    Maecker, H. 2003. Human CD81 directly enhances Th1 and Th2 cell activation, but preferentially induces proliferation of Th2 cells upon long-term stimulation. BMC Immunol.4:1.
    OpenUrlCrossRefPubMed
  87. 87.↵
    Maecker, H., S. C. Todd, and S. Levy. 1997. The tetraspanin superfamily: molecular facilitators. FASEB J.11:428-442.
    OpenUrlCrossRefPubMedWeb of Science
  88. 88.↵
    Manel, N., F. J. Kim, S. Kinet, N. Taylor, M. Sitbon, and J. L. Battini. 2003. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell115:449-459.
    OpenUrlCrossRefPubMedWeb of Science
  89. 89.↵
    Mantegazza, A., M. M. Barrio, S. Moutel, L. Bover,M. Weck, P. Brossart, J. L. Teillaud, and J. Mordoh. 2004. CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells. Blood104:1183-1190.
    OpenUrlAbstract/FREE Full Text
  90. 90.↵
    Marlink, R., P. Kanki, I. Thior, K. Travers, G. Eisen, T. Siby, I. Traore, C. C. Hsieh, M. C. Dia, and E. H. Gueye. 1994. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science265:1587-1590.
    OpenUrlAbstract/FREE Full Text
  91. 91.↵
    Masciopinto, F., S. Campagnoli, S. Abrignani, Y. Uematsu, and P. Pileri. 2001. The small extracellular loop of CD81 is necessary for optimal surface expression of the large loop, a putative HCV receptor. Virus Res.80:1-10.
    OpenUrlCrossRefPubMed
  92. 92.↵
    Masciopinto, F., C. Giovani, S. Campagnoli, L. Galli-Stampino, P. Colombatto, M. Brunetto, T. S. Yen, M. Houghton, P. Pileri, and S. Abrignani. 2004. Association of hepatitis C virus envelope proteins with exosomes. Eur. J. Immunol.34:2834.
    OpenUrlCrossRefPubMedWeb of Science
  93. 93.↵
    Masellis-Smith, A., and A. R. Shaw. 1994. CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin. J. Immunol.152:2768-2777.
    OpenUrlAbstract/FREE Full Text
  94. 94.↵
    McKeating, J. A., L. Q. Zhang, C. Logvinoff, M. Flint, J. Zhang, J. Yu, D. Butera, D. D. Ho, L. B. Dustin, C. M. Rice, and P. Balfe. 2004. Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner. J. Virol.78:8496-8505.
    OpenUrlAbstract/FREE Full Text
  95. 95.↵
    Meerloo, T., H. K. Parmentier, A. D. Osterhaus, J. Goudsmit, and H. J. Schuurman. 1992. Modulation of cell surface molecules during HIV-1 infection of H9 cells. An immunoelectron microscopic study. AIDS6:1105-1116.
    OpenUrlCrossRefPubMed
  96. 96.↵
    Meerloo, T., M. A. Sheikh, A. C. Bloem, A. de Ronde, M. Schutten, C. A. van Els, P. J. Roholl, P. Joling, J. Goudsmit, and H. J. Schuurman. 1993. Host cell membrane proteins on human immunodeficiency virus type 1 after in vitro infection of H9 cells and blood mononuclear cells. An immuno-electron microscopic study. J. Gen. Virol.74:129-135.
    OpenUrlCrossRefPubMed
  97. 97.↵
    Meola, A., A. Sbardellati, B. Bruni Ercole, M. Cerretani, M. Pezzanera, A. Ceccacci, A. Vitelli, S. Levy, A. Nicosia, C. Traboni, J. McKeating, and E. Scarselli. 2000. Binding of hepatitis C virus E2 glycoprotein to CD81 does not correlate with species permissiveness to infection. J. Virol.74:5933-5938.
    OpenUrlAbstract/FREE Full Text
  98. 98.↵
    Min, G., M. Stolz, G. Zhou, F. Liang, P. Sebbel, D. Stoffler, R. Glockshuber, T. T. Sun, U. Aebi, and X. P. Kong. 2002. Localization of uroplakin Ia, the urothelial receptor for bacterial adhesin FimH, on the six inner domains of the 16 nm urothelial plaque particle. J. Mol. Biol.317:697-706.
    OpenUrlCrossRefPubMedWeb of Science
  99. 99.↵
    Miyado, K., G. Yamada, S. Yamada, H. Hasuwa, Y. Nakamura, F. Ryu, K. Suzuki, K. Kosai, K. Inoue, A. Ogura, M. Okabe, and E. Mekada. 2000. Requirement of CD9 on the egg plasma membrane for fertilization. Science287:321-324.
    OpenUrlAbstract/FREE Full Text
  100. 100.↵
    Miyazaki, T., U. Muller, and K. S. Campbell. 1997. Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J.16:4217-4225.
    OpenUrlAbstract
  101. 101.↵
    Mondal, D., L. Pradhan, M. Ali, and K. C. Agrawal. 2004. HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants. Cardiovasc. Toxicol.4:287-302.
    OpenUrlCrossRefPubMed
  102. 102.↵
    Moore, J. P., and R. W. Doms. 2003. The entry of entry inhibitors: a fusion of science and medicine. Proc. Natl. Acad. Sci USA100:10598-10602.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    Moseley, G. W. 2005. Tetraspanin-Fc receptor interactions. Platelets16:3-11.
    OpenUrlCrossRefPubMed
  104. 104.
    Moseley, G. W., J. Elliott, M. D. Wright, L. J. Partridge, and P. N. Monk. 2003. Interspecies contamination of the KM3 cell line: implications for CD63 function in melanoma metastasis. Int. J. Cancer105:613-616.
    OpenUrlCrossRefPubMedWeb of Science
  105. 105.↵
    Murphy, C. G., W. T. Lucas, R. E. Means, S. Czajak, C. L. Hale, J. D. Lifson, A. Kaur, R. P. Johnson, D. M. Knipe, and R. C. Desrosiers. 2000. Vaccine protection against simian immunodeficiency virus by recombinant strains of herpes simplex virus. J. Virol.74:7745-7754.
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    Myszka, D. G., R. W. Sweet, P. Hensley, M. Brigham-Burke, P. D. Kwong, W. A. Hendrickson, R. Wyatt, J. Sodroski, and M. L. Doyle. 2000. Energetics of the HIV gp120-CD4 binding reaction. Proc. Natl. Acad. Sci. USA97:9026-9031.
    OpenUrlAbstract/FREE Full Text
  107. 107.↵
    Nagai, M., M. B. Brennan, J. A. Sakai, C. A. Mora, and S. Jacobson. 2001. CD8+ T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood98:1858-1861.
    OpenUrlAbstract/FREE Full Text
  108. 108.↵
    Nakamura, T., K. Shibayama, K. Nagasato, H. Matsuo, M. Tsujihata, and S. Nagataki. 1990. The efficacy of interferon-alpha treatment in human T-lymphotropic virus type-I-associated myelopathy. Jpn. J. Med.29:362-367.
    OpenUrlPubMed
  109. 109.↵
    Nattermann, J., H. D. Nischalke, B. Kupfer, J. Rockstroh, L. Hess, T. Sauerbruch, and U. Spengler. 2003. Regulation of CC chemokine receptor 5 in hepatitis G virus infection. AIDS17:1457-1462.
    OpenUrlCrossRefPubMedWeb of Science
  110. 110.↵
    Odintsova, E., T. Sugiura, and F. Berditchevski. 2000. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr. Biol.10:1009-1012.
    OpenUrlCrossRefPubMedWeb of Science
  111. 111.↵
    Ono, M., K. Handa, D. A. Withers, and S. Hakomori. 2000. Glycosylation effect on membrane domain (GEM) involved in cell adhesion and motility: a preliminary note on functional α3, α5-CD82 glycosylation complex in IdID 14 cells. Biochem. Biophys. Res. Commun.279:744-750.
    OpenUrlCrossRefPubMedWeb of Science
  112. 112.↵
    Ono, M., K. Handa, D. A. Withers, and S. Hakomori. 1999. Motility inhibition and apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9, with concurrent glycosylation. Cancer Res.59:2335-2339. 113. Reference deleted.
    OpenUrlAbstract/FREE Full Text
  113. 114.↵
    Orenstein, J. M., M. S. Meltzer, T. Phipps, and H. E. Gendelman. 1988. Cytoplasmic assembly and accumulation of human immunodeficiency virus types 1 and 2 in recombinant human colony-stimulating factor-1-treated human monocytes: an ultrastructural study. J. Virol.62:2578-2586.
    OpenUrlAbstract/FREE Full Text
  114. 115.↵
    Palella, F. J., Jr., K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer, G. A. Satten, D. J. Aschman, and S. D. Holmberg. 1998. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N. Engl. J. Med.338:853-860.
    OpenUrlCrossRefPubMedWeb of Science
  115. 116.↵
    Parren, P. W., J. P. Moore, D. R. Burton, and Q. J. Sattentau. 1999. The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity. AIDS13(Suppl. A):S137-S162.
    OpenUrlPubMedWeb of Science
  116. 117.↵
    Pelchen-Matthews, A., B. Kramer, and M. Marsh. 2003. Infectious HIV-1 assembles in late endosomes in primary macrophages. J. Cell Biol.162:443-455.
    OpenUrlAbstract/FREE Full Text
  117. 118.↵
    Penas, P., A. Garcia-Diez, F. Sanchez-Madrid, and M. Yanez-Mo. 2000. Tetraspanins are localized at motility-related structures and involved in normal human keratinocyte wound healing migration. J. Investig. Dermatol.114:1126-1135.
    OpenUrlCrossRefPubMedWeb of Science
  118. 119.↵
    Perez-Bercoff, D., A. David, H. Sudry, F. Barré-Sinoussi, and G. Pancino. 2003. Fcγ receptor-mediated suppression of human immunodeficiency virus type 1 replication in primary human macrophages. J. Virol.77:4081-4094.
    OpenUrlAbstract/FREE Full Text
  119. 120.↵
    Petracca, R., F. Falugi, G. Galli, N. Norais, D. Rosa, S. Campagnoli, V. Burgio, E. Di Stasio, B. Giardina, M. Houghton, S. Abrignani, and G. Grandi. 2000. Structure-function analysis of hepatitis C virus envelope-CD81 binding. J. Virol.74:4824-4830.
    OpenUrlAbstract/FREE Full Text
  120. 121.↵
    Phillips, A. 2001. Will the drugs still work? Transmission of resistant HIV. Nat. Med.7:993-994.
    OpenUrlCrossRefPubMedWeb of Science
  121. 122.↵
    Pileri, P., Y. Uematsu, S. Campagnoli, G. Galli, F. Falugi, R. Petracca, A. J. Weiner, M. Houghton, D. Rosa, G. Grandi, and S. Abrignani. 1998. Binding of hepatitis C virus to CD81. Science282:938-941.
    OpenUrlAbstract/FREE Full Text
  122. 123.↵
    Pinon, J. D., P. J. Klasse, S. R. Jassal, S. Welson, J. Weber, D. W. Brighty, and Q. J. Sattentau. 2003. Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J. Virol.77:9922-9930.
    OpenUrlAbstract/FREE Full Text
  123. 124.↵
    Pique, C., C. Lagaudriere-Gesbert, L. Delamarre, A. R. Rosenberg, H. Conjeaud, and M. C. Dokhelar. 2000. Interaction of CD82 tetraspanin proteins with HTLV-1 envelope glycoproteins inhibits cell-to-cell fusion and virus transmission. Virology276:455-465.
    OpenUrlCrossRefPubMed
  124. 125.↵
    Poduri, C. D. 2003. Hepatitis C virus (HCV)[em]a review molecular biology of the virus, immunodiagnostics, genomic heterogeneity and the role of virus in hepatocellular carcinoma. Indian J. Exp. Biol.41:549-562.
    OpenUrlPubMed
  125. 126.↵
    Pohlmann, S., J. Zhang, F. Baribaud, Z. Chen, G. J. Leslie, G. Lin, A. Granelli-Piperno, R. W. Doms, C. M. Rice, and J. A. McKeating. 2003. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J. Virol.77:4070-4080.
    OpenUrlAbstract/FREE Full Text
  126. 127.↵
    Preston, B. D. 1997. Reverse transcriptase fidelity and HIV-1 variation. Science275:228-231.
    OpenUrlCrossRefPubMed
  127. 128.↵
    Raposo, G., M. Moore, D. Innes, R. Leijendekker, A. Leigh-Brown, P. Benaroch, and H. Geuze. 2002. Human macrophages accumulate HIV-1 particles in MHC II compartments. Traffic3:718-729.
    OpenUrlCrossRefPubMedWeb of Science
  128. 129.
    Rice, C. M. 1999. Is CD81 the key to hepatitis C virus entry? Hepatology29:990-992.
    OpenUrlCrossRefPubMed
  129. 130.↵
    Richardson, J. H., A. J. Edwards, J. K. Cruickshank, P. Rudge, and A. G. Dalgleish. 1990. In vivo cellular tropism of human T-cell leukemia virus type 1. J. Virol.64:5682-5687.
    OpenUrlAbstract/FREE Full Text
  130. 131.↵
    Roccasecca, R., H. Ansuini, A. Vitelli, A. Meola, E. Scarselli, S. Acali, M. Pezzanera, B. B. Ercole, J. McKeating, A. Yagnik, A. Lahm, A. Tramontano, R. Cortese, and A. Nicosia. 2003. Binding of the hepatitis C virus E2 glycoprotein to CD81 is strain specific and is modulated by a complex interplay between hypervariable regions 1 and 2. J. Virol.77:1856-1867.
    OpenUrlAbstract/FREE Full Text
  131. 132.↵
    Rosa, D. 1996. E2 binds to chimpanzee mononuclear cells, whereas it does not bind to rat, rabbit, or green monkey mononuclear cells or hepatocytes. Proc. Natl. Acad. Sci. USA93:1759.
    OpenUrlAbstract/FREE Full Text
  132. 133.↵
    Rose, N. F., P. A. Marx, A. Luckay, D. F. Nixon, W. J. Moretto, S. M. Donahoe, D. Montefiori, A. Roberts, L. Buonocore, and J. K. Rose. 2001. An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell106:539-549.
    OpenUrlCrossRefPubMedWeb of Science
  133. 134.↵
    Rubinstein, E., F. Le Naour, M. Billard, M. Prenant, C. Boucheix. 1994. CD9 antigen is an accessory subunit of the VLA integrin complexes. Eur. J. Immunol.24:3005-3013.
    OpenUrlCrossRefPubMedWeb of Science
  134. 135.↵
    Rubinstein, E., F. Le Naour, C. Lagaudriere-Gesbert, M. Billard, H. Conjeaud, C. Boucheix. 1996. CD9, CD63, CD81, and CD82 are components of a surface tetraspan network connected to HLA-DR and VLA integrins. Eur. J. Immunol.26:2657-2665.
    OpenUrlCrossRefPubMedWeb of Science
  135. 136.↵
    Sakuma, T., S. Higashiyama, S. Hosoe, S. Hayashi, and N. Taniguchi. 1997. CD9 antigen interacts with heparin-binding EGF-like growth factor through its heparin-binding domain. J. Biochem.122:474-480.
    OpenUrlCrossRefPubMed
  136. 137.↵
    Sasaki, M., K. Yamauchi, T. Nakanishi, Y. Kamogawa, and N. Hayashi. 2003. In vitro binding of hepatitis C virus to CD81-positive and -negative human cell lines. J. Gastroenterol. Hepatol.18:74-79.
    OpenUrlCrossRefPubMed
  137. 138.↵
    Satomi, Y., Y. Shimonishi, and T. Takao. 2004. N-glycosylation at Asn491 in the Asn-Xaa-Cys motif of human transferrin. FEBS Lett.576:51-56.
    OpenUrlCrossRefPubMedWeb of Science
  138. 139.↵
    Scarselli, E., H. Ansuini, R. Cerino, R. M. Roccasecca, S. Acali, G. Filocamo, C. Traboni, A. Nicosia, R. Cortese, and A. Vitelli. 2002. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J.21:5017-5025.
    OpenUrlAbstract
  139. 140.↵
    Scherberich, A., G. Giannone, E. Perennou, K. Takeda, C. Boucheix, E. Rubinstein, F. Lanza, and A. Beretz. 2002. FAK-mediated inhibition of vascular smooth muscle cell migration by the tetraspanin CD9. Thromb. Haemostasis87:1043-1050.
    OpenUrlPubMedWeb of Science
  140. 141.↵
    Schmid, E., A. Zurbriggen, U. Gassen, B. Rima, V. ter Meulen, and J. Schneider-Schaulies. 2000. Antibodies to CD9, a tetraspan transmembrane protein, inhibit canine distemper virus-induced cell-cell fusion but not virus-cell fusion. J. Virol.74:7554-7561.
    OpenUrlAbstract/FREE Full Text
  141. 142.↵
    Seigneuret, M., A. Delaguillaumie, C. Lagaudriere-Gesbert, and H. Conjeaud. 2001. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J. Biol. Chem.276:40055-40064.
    OpenUrlAbstract/FREE Full Text
  142. 143.↵
    Shaw, A., A. Domanska, A. Mak, A. Gilchrist, K. Dobler, L. Visser, S. Poppema, L. Fliegel, M. Letarte, and B. J. Willett. 1995. Ectopic expression of human and feline CD9 in a human B cell line confers beta 1 integrin-dependent motility on fibronectin and laminin substrates and enhanced tyrosine phosphorylation. J. Biol. Chem.270:24092-24099.
    OpenUrlAbstract/FREE Full Text
  143. 144.↵
    Shi, W., H. Fan, L. Shum, and R. Derynck. 2000. The tetraspanin CD9 associates with transmembrane TGF-alpha and regulates TGF-alpha-induced EGF receptor activation and cell proliferation. J. Cell Biol.148:591-602.
    OpenUrlAbstract/FREE Full Text
  144. 145.↵
    Shibayama, K., T. Nakamura, K. Nagasato, S. Shirabe, M. Tsujihata, and S. Nagataki. 1991. Interferon-alpha treatment in HTLV-I-associated myelopathy. Studies of clinical and immunological aspects. J. Neurol. Sci.106:186-192.
    OpenUrlCrossRefPubMed
  145. 146.↵
    Shiver, J. W., T. M. Fu, L. Chen, D. R. Casimiro, M. E. Davies, R. K. Evans, Z. Q. Zhang, A. J. Simon, W. L. Trigona, S. A. Dubey, L. Huang, V. A. Harris, R. S. Long, X. Liang, L. Handt, W. A. Schleif, L. Zhu, D. C. Freed, N. V. Persaud, L. Guan, K. S. Punt, A. Tang, M. Chen, K. A. Wilson, K. B. Collins, G. J. Heidecker, V. R. Fernandez, H. C. Perry, J. G. Joyce, K. M. Grimm, J. C. Cook, P. M. Keller, D. S. Kresock, H. Mach, R. D. Troutman, L. A. Isopi, D. M. Williams, Z. Xu, K. E. Bohannon, D. B. Volkin, D. C. Montefiori, A. Miura, G. R. Krivulka, M. A. Lifton, M. J. Kuroda, J. E. Schmitz, N. L. Letvin, M. J. Caulfield, A. J. Bett, R. Youil, D. C. Kaslow, and E. A. Emini. 2002. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature415:331-335.
    OpenUrlCrossRefPubMedWeb of Science
  146. 147.↵
    Silvie, O., E. Rubinstein, J. F. Franetich, M. Prenant, E. Belnoue, L. Renia, L. Hannoun, W. Eling, S. Levy, C. Boucheix, and D. Mazier. 2003. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nat. Med.9:93-96.
    OpenUrlCrossRefPubMedWeb of Science
  147. 148.↵
    Simon, F., S. Matheron, C. Tamalet, I. Loussert-Ajaka, S. Bartczak, J. M. Pepin, C. Dhiver, E. Gamba, C. Elbim, and J. A. Gastaut. 1993. Cellular and plasma viral load in patients infected with HIV-2. AIDS7:1411-1417.
    OpenUrlCrossRefPubMedWeb of Science
  148. 149.↵
    Simons, K., and E. Ikonen. 1997. Functional rafts in cell membranes. Nature387:569-572.
    OpenUrlCrossRefPubMedWeb of Science
  149. 150.
    Sincock, P., G. Mayrhofer, and L. K. Ashman. 1997. Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and α5β1 integrin. J. Histochem. Cytochem.45:515-525.
    OpenUrlCrossRefPubMedWeb of Science
  150. 151.↵
    Song, B., S. Levy, and E. E. Geisert, Jr. 2004. Increased density of retinal pigment epithelium in cd81−/− mice. J. Cell. Biochem.92:1160-1170.
    OpenUrlCrossRefPubMed
  151. 152.↵
    Stipp, C., T. V. Kolesnikova, and M. E. Hemler. 2003. Functional domains in tetraspanin proteins. Trends Biochem. Sci.28:106-112.
    OpenUrlCrossRefPubMedWeb of Science
  152. 153.↵
    Sutton, R. E., and D. R. Littman. 1996. Broad host range of human T-cell leukemia virus type 1 demonstrated with an improved pseudotyping system. J. Virol.70:7322-7336.
    OpenUrlAbstract/FREE Full Text
  153. 154.↵
    Szollosi, J., V. Horejsi, L. Bene, P. Angelisova, and S. Damjanovich. 1996. Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. J. Immunol.157:2939-2946.
    OpenUrlAbstract
  154. 155.↵
    Tachibana, I., and M. E. Hemler, M. E. 1999. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J. Cell Biol.146:893-904.
    OpenUrlAbstract/FREE Full Text
  155. 156.↵
    Tan, Y. J., S. P. Lim, P. Ng, P. Y. Goh, S. G. Lim, Y. H. Tan, and W. Hong. 2003. CD81 engineered with endocytotic signals mediates HCV cell entry: implications for receptor usage by HCV in vivo. Virology308:250-269.
    OpenUrlCrossRefPubMed
  156. 157.↵
    Teoh, N. C., and G. C. Farrell. 2004. Management of chronic hepatitis C virus infection: a new era of disease control. Intern. Med. J.34:324-337.
    OpenUrlCrossRefPubMed
  157. 158.↵
    Trejo, S. R., and L. Ratner. 2000. The HTLV receptor is a widely expressed protein. Virology268:41-48.
    OpenUrlCrossRefPubMed
  158. 159.↵
    Tseng, C. T., and G. R. Klimpel. 2002. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med.195:43-49.
    OpenUrlCrossRefPubMedWeb of Science
  159. 160.↵
    VanCompernolle, S. E., A. V. Wiznycia, J. R. Rush, M. Dhanasekaran, P. W. Baures, and S. C. Todd. 2003. Small molecule inhibition of hepatitis C virus E2 binding to CD81. Virology314:371-380.
    OpenUrlCrossRefPubMedWeb of Science
  160. 161.↵
    von Lindern, J. J., D. Rojo, K. Grovit-Ferbas, C. Yeramian, C. Deng, G. Herbein, M. R. Ferguson, T. C. Pappas, J. M. Decker, A. Singh, R. G. Collman, and W. A. O'Brien. 2003. Potential role for CD63 in CCR5-mediated human immunodeficiency virus type 1 infection of macrophages. J. Virol.77:3624-3633.
    OpenUrlAbstract/FREE Full Text
  161. 162.↵
    Watanabe, M. E. 2003. Skeptical scientists skewer VaxGen statistics. Nat. Med.9:376.
    OpenUrlPubMedWeb of Science
  162. 163.↵
    Willett, B., M. Hosie, A. Shaw, and J. Neil. 1997. Inhibition of feline immunodeficiency virus infection by CD9 antibody operates after virus entry and is independent of virus tropism. J. Gen. Virol.78:611-618.
    OpenUrlPubMed
  163. 164.↵
    Willett, B. J., M. J. Hosie, O. Jarrett, and J. C. Neil. 1994. Identification of a putative cellular receptor for feline immunodeficiency virus as the feline homologue of CD9. Immunology81:228-233.
    OpenUrlPubMedWeb of Science
  164. 165.
    Wollscheid, V., R. Kuhne-Heid, I. Stein, L. Jansen, S. Kollner, A. Schneider, and M. Durst. 2002. Identification of a new proliferation-associated protein NET-1/C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas. Int. J. Cancer.99:771-775.
    OpenUrlCrossRefPubMedWeb of Science
  165. 166.↵
    Wright, M., S. M. Geary, S. Fitter, G. W. Moseley, L. M. Lau, K. C. Sheng, V. Apostolopoulos, E. G. Stanley, D. E. Jackson, and L. Ashman. 2004. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol. Cell. Biol.24:5978-5988.
    OpenUrlAbstract/FREE Full Text
  166. 167.↵
    Wright, M., G. W. Moseley, and A. B. VanSpriel. 2004. Tetraspanin microdomains in immune cell signalling and malignant disease. Tissue Antigens64:533-542.
    OpenUrlCrossRefPubMedWeb of Science
  167. 168.↵
    Wright, M., and M. Tomlinson. 1994. The ins and outs of the transmembrane-4 superfamily. Immunol. Today15:588-594.
    OpenUrlCrossRefPubMedWeb of Science
  168. 169.↵
    Wubbolts, R., R. S. Leckie, P. T. Veenhuizen, G. Schwarzmann, W. Mobius, J. Hoernschemeyer, J. W. Slot, H. J. Geuze, and W. Stoorvogel. 2003. Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. J. Biol. Chem.278:10963-10972.
    OpenUrlAbstract/FREE Full Text
  169. 170.↵
    Wunschmann, S., J. D. Medh, D. Klinzmann, W. N. Schmidt, and J. T. Stapleton. 2000. Characterization of hepatitis C virus (HCV) and HCV E2 interactions with CD81 and the low-density lipoprotein receptor. J. Virol.74:10055-10062.
    OpenUrlAbstract/FREE Full Text
  170. 171.↵
    Yamasaki, K., J. Kira, Y. Koyanagi, Y. Kawano, N. Miyano-Kurosaki, M. Nakamura, E. Baba, J. Suzuki, A. Yamamoto, N. Yamamoto, and T. Kobayashi. 1997. Long-term, high dose interferon-alpha treatment in HTLV-I-associated myelopathy/tropical spastic paraparesis: a combined clinical, virological and immunological study. J. Neurol. Sci.147:135-144.
    OpenUrlCrossRefPubMedWeb of Science
  171. 172.↵
    Yauch, R., and M. E. Hemler. 2000. Specific interactions among transmembrane 4 superfamily (TM4SF) proteins and phosphoinositide 4-kinase. Biochem. J.351:629-637.
    OpenUrlAbstract/FREE Full Text
  172. 173.↵
    Yauch, R., A. R. Kazarov, B. Desai, R. T. Lee, and M. E. Hemler. 2000. Direct extracellular contact between integrin α3β1 and TM4SF protein CD151. J. Biol. Chem.275:9230-9238.
    OpenUrlAbstract/FREE Full Text
  173. 174.
    Zemni, R., T. Bienvenu, M. C. Vinet, A. Sefiani, A. Carrié, A., P. Billuart, N. McDonell, P. Couvert, F. Francis, P. Chafey, F. Fauchereau, G. Friocourt, V. des Portes, A. Cardona, S. Frints, A. Meindl, O. Brandau, N. Ronce, C. Moraine, H. van Bokhoven, H. H. Ropers, R. Sudbrak, A. Kahn, J. P. Fryns, C. Beldjord, and J. Chelly. 2000. A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nat. Genet.24:167-170.
    OpenUrlCrossRefPubMedWeb of Science
  174. 175.↵
    Zhang, J., G. Randall, A. Higginbottom, P. Monk, C. M. Rice, and J. A. McKeating. 2004. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J. Virol.78:1448-1455.
    OpenUrlAbstract/FREE Full Text
  175. 176.↵
    Zhang, X., A. L. Bontrager, and M. E. Hemler. 2001. Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific β1 integrins. J. Biol. Chem.276:25005-25013.
    OpenUrlAbstract/FREE Full Text
Back to top
Download PDF
Citation Tools
Print

Alerts
Email

KEYWORDS

Membrane Glycoproteins
Receptors, Virus
Virus Diseases

Related Articles

Cited By...