Soluble recombinant HTLV-1 surface glycoprotein competitively inhibits syncytia formation and viral infection of cells

Jassal, Sushma R.; Lairmore, Michael Dale; Leigh-Brown, Andrew J.; Brighty, David W.

doi:10.1016/s0168-1702(01)00279-9

Cited by 22 publications

(32 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lymphocytes naturally infected with HTLV-1 produce very few cell-free HTLV-1 virions, and one in 10 5 to 10 6 virions is estimated to be infectious [38,39]. The cell-to-cell spread of HTLV-1 is mediated through fusion of the two cell membranes caused by Env proteins [23,47,48]. Certain integrins, including the intercellular and vascular cell adhesion molecules ICAM-1, ICAM-3, and 13 VCAM, act as cofactors for HTLV-1-induced cell fusion [49,50] Luciferase activity increased linearly with the number of MT-2 cells, up to 5x10 4 cells.…”

Section: Fusion Ability Of Htlv-1-infected Rat Cellsmentioning

confidence: 99%

CRM1, an RNA transporter, is a major species-specific restriction factor of human T cell leukemia virus type 1 (HTLV-1) in rat cells

Zhang

Hakata

Tanaka

et al. 2006

Microbes and Infection

View full text Add to dashboard Cite

Rat ortholog of human CRM1 has been found to be responsible for the poor activity of viral Rex protein, which is essential for RNA export of human T cell leukemia virus type 1 (HTLV-1). Here, we examined species-specific barrier of HTLV-1 by establishing rat cell lines, including both adherent and CD4 + T cells, which express human CRM1 at physiological levels. We demonstrated that expression of human CRM1 in rat cells is not harmful to cell growth and is sufficient to restore the synthesis of the viral structural proteins, Gag and Env, at levels similar to those in human cells. Gag precursor proteins were efficiently processed to the mature forms in rat cells and released into the culture medium as sedimentable viralparticles. An HTLV-1 pseudovirus infection system suggested that the released virus particles are fully infectious. Our newly developed reporter cell system revealed that Env proteins produced in rat cells are fully fusogenic, which is the basis for cell-cell HTLV-1 infection.Moreover, we show that the early steps in infection, from post-entry uncoating to integration into the host chromosomes, occur efficiently in rat cells. These results, in conjunction with reports describing efficient entry of HTLV-1 into rat cells, may indicate that HTLV-1 is unique in that its major species-specific barrier is determined by CRM1 at a viral RNA export step.These observations will enable us to construct a transgenic rat model expressing human CRM1 that is sensitive to HTLV-1 infection.

show abstract

Section: Fusion Ability Of Htlv-1-infected Rat Cellsmentioning

confidence: 99%

CRM1, an RNA transporter, is a major species-specific restriction factor of human T cell leukemia virus type 1 (HTLV-1) in rat cells

Zhang

Hakata

Tanaka

et al. 2006

Microbes and Infection

View full text Add to dashboard Cite

show abstract

“…HTLV-1 infection is dependent upon the viral envelope glycoprotein-catalyzed fusion of the viral and cellular membranes. 18) Like many other retroviruses, HTLV-1 can induce syncytium formation between infected cells and certain uninfected cell types. Thus, to determine whether As 2 O 3 -treatment inhibits HTLV-1 transmission, we first carried out a syncytium formation assay using As 2 O 3 -treated MT-2 cells and uninfected HeLa cells.…”

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Inhibits Human T Cell-Lymphotropic Virus-1-Induced Syncytiums by Down-Regulating gp46

Nabeshi

Yoshikawa

Kamada

et al. 2009

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL).1,2) ATL is characterized by malignant lympho-proliferation of mature activated T cells, predominantly CD4-positive T cells. This proliferation develops after a long period of latency following HTLV-1 infection. It is currently estimated that there are about twenty million HTLV-1 carriers worldwide. Of these, around 5% are at risk for ATL onset, and it has been reported that the incidence of ATL has been increasing. Epidemiological studies have indicated strongly that an increased HTLV-1 virus load is an important factor in ATL onset, although the detailed mechanisms of ATL onset are unknown. Therefore, an ideal anti-ATL agent would have both a growth inhibitory effect on ATL cells and an inhibitory effect on transmission of HTLV-1-infected cells. As 2 O 3 show promising results in the treatment of patients with ATL in combination with interferon (IFN)-a. [3][4][5][6][7][8] Although As 2 O 3 -induced apoptosis is thought to play a major role in its observed therapeutic growth inhibitory effects in treating ATL 9,10) the effects of As 2 O 3 on HTLV-1 infection/transmission have not been reported.HTLV-1 can be distinguished from all other retroviruses on the basis of the infection process: it is transmitted almost exclusively via cell-to-cell contact and cell-to-cell fusion (also termed syncytium formation), and the free viral particle is very poorly infectious.11) The HTLV-1 envelope glycoprotein is synthesized as a 61-kDa precursor that is cleaved into cellsurface (gp46) and transmembrane (gp21) proteins 12,13) and the gp46 product is thought to play an important role as the virus attachment protein. HTLV-1 can induce syncytium formation between infected cells and certain uninfected cell types 14,15) but this process can be blocked by antibodies against the gp46 protein or against gp46-derived peptides. 16,17) Thus, gp46 is a key protein for HTLV-1 transmission via syncytium formation, which is a critical process for HTLV-1 transmission via cell-to-cell contact.In the present study, we reveal that HTLV-1-induced syncytium formation can be blocked by As 2 O 3 treatment. Western blot analysis indicated that gp46 was down-regulated by As 2 O 3 treatment. Our results suggest that As 2 O 3 can prevent the HTLV-1 transmission by reducing levels of gp46, in addition to its therapeutic effect on ATL by promoting apoptosis. These results suggested that As 2 O 3 may open new avenues for treating HTLV-1-related diseases, including ATL. MATERIALS AND METHODS Cell CultureThe HTLV-1-infected cell line MT-2 (a kind gift from Hayashibara Biochemical Laboratories, Inc.) was grown in RPMI-1640 (Wako Pure Chemical Industries, Ltd., Osaka, Japan) supplemented with 10% heat-inactivated fetal calf serum and 1% Antibiotic-Antimycotic Mix stock solution (Nacalai Tesque, Osaka, Japan) in a humidified atmosphere of 95% air/5% CO 2 , at 37°C. A HeLa cell line was maintained in minimum essential medium (MEM-a; Wako) supplemented with 10% heat-...

show abstract

“…Syncytium Interference Assay-Syncytium interference assays were performed by standard methods (26,27). HeLa cells (3 ϫ 10 5 ) transfected with the envelope expression vector pHTE-1 were added to untransfected HeLa target cells (7.0 ϫ 10 5 ).…”

Section: Methodsmentioning

confidence: 99%

“…Pseudotyping Assay-Pseudotyped virus was prepared as described (27). Briefly, 293T cells were co-transfected using FuGENE 6 with 10 g of the Env-defective, luciferase-encoding HIV proviral clone pNL4-3.LUC.R…”

Section: Methodsmentioning

confidence: 99%

Resistance to Neutralization by Antibodies Targeting the Coiled Coil of Fusion-active Envelope Is a Common Feature of Retroviruses

Mirsaliotis

Nurkiyanova

Lamb

et al. 2007

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The human T-cell leukemia virus transmembrane glycoprotein (TM) is a typical class 1 membrane fusion protein and a subunit of the viral envelope glycoprotein complex. Following activation, the TM undergoes conformational transitions from a native nonfusogenic state to a fusion-active pre-hairpin intermediate that subsequently resolves to a compact trimer-of-hairpins or six-helix bundle. Disruption of these structural transitions inhibits membrane fusion and viral entry and validates TM as an anti-viral and vaccine target. To investigate the immunological properties of fusion-active TM, we have generated a panel of monoclonal antibodies that recognize the coiled-coil domain of the pre-hairpin intermediate. Antibody reactivity is highly sensitive to the conformation of the coiled coil as binding is dramatically reduced or lost on denatured antigen. Moreover, a unique group of antibodies are 100 -1000-fold more reactive with the coiled coil than the trimer-of-hairpins form of TM. The antibodies recognize virally expressed envelope, and significantly, some selectively bind to envelope only under conditions that promote membrane fusion. Most importantly, many of the antibodies potently block six-helix bundle formation in vitro. Nevertheless, viral envelope was remarkably resistant to neutralization by antibodies directed to the coiled coil. The data imply that the coiled coil of viral envelope is poorly exposed to antibody during membrane fusion. We suggest that resistance to neutralization by antibodies directed to fusion-associated structures is a common property of retroviral TM and perhaps of other viral class I fusion proteins. These observations have significant implications for vaccine design.

show abstract

Soluble recombinant HTLV-1 surface glycoprotein competitively inhibits syncytia formation and viral infection of cells

Cited by 22 publications

References 53 publications

CRM1, an RNA transporter, is a major species-specific restriction factor of human T cell leukemia virus type 1 (HTLV-1) in rat cells

CRM1, an RNA transporter, is a major species-specific restriction factor of human T cell leukemia virus type 1 (HTLV-1) in rat cells

Arsenic Trioxide Inhibits Human T Cell-Lymphotropic Virus-1-Induced Syncytiums by Down-Regulating gp46

Resistance to Neutralization by Antibodies Targeting the Coiled Coil of Fusion-active Envelope Is a Common Feature of Retroviruses

Contact Info

Product

Resources

About