Immunopathology Associated with Human Lymphotropic Retroviruses

Ruscetti, Francis W.

doi:10.1159/000156975

Cited by 3 publications

(4 citation statements)

References 54 publications

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“…The fact that VCAM-1 can mediate syncytium formation by HTLV-1 raises the possibility that VCAM-1 can serve as a receptor for this virus. HTLV-1 shows tropism for a wide variety of cell types, including cells from nonhuman species (9,12,29,32,55,56,70,72). Given the restricted expression of VCAM-1, which is limited primarily to endothelial cells and a few other cell types (49), it is very unlikely that VCAM-1 is the principal receptor for HTLV-1.…”

Section: Discussionmentioning

confidence: 99%

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

Hildreth

Subramanium

Hampton

1997

J Virol

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While studying the potential role of vascular cell adhesion molecule-1 (VCAM-1) in infection of endothelial cells by human immunodeficiency virus (HIV), we found that VCAM-1 can mediate human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation. Both expression-vector-encoded and endogenously expressed VCAM-1 supported fusion of uninfected cells with HTLV-1-infected cells. Fusion was obtained with cell lines carrying the HTLV-1 genome and expressing viral proteins but not with an HTLV-1-transformed cell line that does not express viral proteins. In clones of VCAM-1-transfected cells, the degree of syncytium formation observed directly reflected the level of VCAM-1 expression. Syncytium formation between HTLV-1-expressing cells and VCAM-1 ؉ cells could be blocked with antiserum against HTLV-1 gp46 and with a monoclonal antibody (MAb) against VCAM-1. Fusion was not blocked by antiserum against HIV or a MAb against VLA-4, the physiological counter-receptor for VCAM-1. The results indicate that VCAM-1 can serve as an accessory molecule or potential coreceptor for HTLV-1-induced cell fusion and provide direct evidence of a role for cell adhesion molecules in the biology of HTLV-1. Human T-cell lymphotropic virus type 1 (HTLV-1) is a type C retrovirus and the etiologic agent of adult T-cell leukemia (52, 65, 69) and HTLV-1-associated myelopathy or tropical spastic paraparesis (21, 23, 58, 71). HTLV-1 shows tropism primarily for T cells but infects a variety of cell types, including cells from some nonhuman species (9, 12, 29, 32, 55, 56, 70, 72). Infectivity by free HTLV-1 tends to be very poor, and the virus appears to be transmitted most efficiently by the cell-tocell route (43). The HTLV-1 envelope glycoprotein is synthesized as a 61-kDa precursor which is cleaved into cell-surface (gp46) and transmembrane (gp21) proteins (45, 66). gp46 is thought to serve as the virus attachment protein, as does gp120 for human immunodeficiency virus (HIV) (45, 66). Although previous reports have identified host cell molecules which potentially mediate virus binding (12, 19), the cellular receptor for HTLV-1 has not been definitively identified. gp21 is likely to serve as a fusion protein through its N-terminal hydrophobic domain in a manner similar to that of HIV gp41, which contains an N-terminal fusion domain (16, 71). Like many other retroviruses, HTLV-1 can induce syncytium formation between infected cells and certain uninfected cell types (31, 44). This syncytium formation can be blocked by antibodies against the HTLV-1 envelope protein (50). Like HTLV-1, syncytium formation induced by HIV type 1 (HIV-1) is also inhibited by antibodies against its envelope proteins gp120 and gp41 (27, 59). CD4 has been identified as the principal receptor of HIV, and antibodies against this molecule inhibit HIV-induced syncytium formation (39, 42). We previously demonstrated that HIV-1-induced syncytium formation can be blocked by anti-MATERIALS AND METHODS Cells. The following cell lines were obtained from the American Type ...

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Section: Discussionmentioning

confidence: 99%

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

Hildreth

Subramanium

Hampton

1997

J Virol

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“…These are protease (PR), reverse transcriptase (RT), and integrase (IN) (Ruscetti, 1985;Kohl et al, 1988;LaFemina et al, 1992). As inactivating any of these enzymes may negate the infectivity of HIV-1, the enzymes have been targets of anti-retroviral drug development.…”

Section: Introductionmentioning

confidence: 99%

“…Human immunodeficiency virus type 1 (HIV-1), causative agent of acquired immunodeficiency syndrome (AIDS), possesses three critical enzymes for replication. These are protease (PR), reverse transcriptase (RT), and integrase (IN) (Ruscetti, 1985;Kohl et al, 1988;LaFemina et al, 1992). As inactivating any of these enzymes may negate the infectivity of HIV-1, the enzymes have been targets of anti-retroviral drug development.…”

Section: Introductionmentioning

confidence: 99%

A Novel Small Molecular Weight Compound with a Carbazole Structure That Demonstrates Potent Human Immunodeficiency Virus Type-1 Integrase Inhibitory Activity

Yan

Mizutani

Nomura

et al. 2005

Antivir Chem Chemother

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The integration of reverse transcribed proviral DNA into a host genome is an essential event in the human immunodeficiency virus type 1 (HIV-1) replication life cycle. Therefore, the viral enzyme integrase (IN), which plays a crucial role in the integration event, has been an attractive target of anti-retroviral drugs. Several IN inhibitory compounds have been reported previously, yet none has been successful in clinical use. To find a new, more successful IN inhibitor, we screened a diverse library of 12 000 small molecular weight compounds randomly by in vitro strand-transfer assay. We identified a series of substituted carbazoles that exhibit strand-transfer inhibitory activity at low micromolar concentrations. Of these, the most potent compound exhibited an IC50 of 5.00+/-3.31 microM (CA-0). To analyse the structural determinants of strand-transfer inhibitory activity of the carbazole derivatives, we selected 23 such derivatives from our compound library and performed further analyses. Of these 23 compounds, six showed strong strand-transfer inhibition. The inhibition kinetics analyses and ethidium bromide displacement assays indicated that the carbazole derivatives are competitive inhibitors and not intercalators. An HeLa4.5/LTR-nEGFP cell line was employed to evaluate in vitro virus replication inhibition of the carbazole derivatives, and IC50 levels ranged from 0.48-1.52 microM. Thus, it is possible that carbazole derivatives, which possess structures different from previously-reported IN inhibitors, may become novel lead compounds in the development of IN inhibitors.

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“…Human T-cell lymphotropic virus type 1 (HTLV-1) is a type C retrovirus and the etiologic agent of adult T-cell leukemia (43,56,59) and HTLV-1-associated myelopathy or tropical spastic paraparesis (15,17,49,61). Although HTLV-1 shows tropism primarily for T cells, it can infect a variety of cell types including cells from some nonhuman species (6,9,27,46,48,60,62). Infection by free HTLV-1 tends to be highly inefficient, and the virus appears to be transmitted primarily by the cellto-cell route (37).…”

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confidence: 99%

Syncytium-Inhibiting Monoclonal Antibodies Produced against Human T-Cell Lymphotropic Virus Type 1-Infected Cells Recognize Class II Major Histocompatibility Complex Molecules and Block by Protein Crowding

Hildreth

1998

J Virol

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Four new monoclonal antibodies (MAbs) that inhibit human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation were produced by immunizing BALB/c mice with HTLV-1-infected MT2 cells. Immunoprecipitation studies and binding assays of transfected mouse cells showed that these MAbs recognize class II major histocompatibility complex (MHC) molecules. Previously produced anti-class II MHC antibodies also blocked HTLV-1-induced cell fusion. Coimmunoprecipitation and competitive MAb binding studies indicated that class II MHC molecules and HTLV-1 envelope glycoproteins are not associated in infected cells. Anti-MHC antibodies had no effect on human immunodeficiency virus type 1 (HIV-1) syncytium formation by cells coinfected with HIV-1 and HTLV-1, ruling out a generalized disruption of cell membrane function by the antibodies. High expression of MHC molecules suggested that steric effects of bound anti-MHC antibodies might explain their inhibition of HTLV-1 fusion. An anti-class I MHC antibody and a polyclonal antibody consisting of several nonblocking MAbs against other molecules bound to MT2 cells at levels similar to those of class II MHC antibodies, and they also blocked HTLV-1 syncytium formation. Dose-response experiments showed that inhibition of HTLV-1 syncytium formation correlated with levels of antibody bound to the surface of infected cells. The results show that HTLV-1 syncytium formation can be blocked by protein crowding or steric effects caused by large numbers of immunoglobulin molecules bound to the surface of infected cells and have implications for the structure of the cellular HTLV-1 receptor(s).

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Immunopathology Associated with Human Lymphotropic Retroviruses

Cited by 3 publications

References 54 publications

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

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

A Novel Small Molecular Weight Compound with a Carbazole Structure That Demonstrates Potent Human Immunodeficiency Virus Type-1 Integrase Inhibitory Activity

Syncytium-Inhibiting Monoclonal Antibodies Produced against Human T-Cell Lymphotropic Virus Type 1-Infected Cells Recognize Class II Major Histocompatibility Complex Molecules and Block by Protein Crowding

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