The membrane-proximal tryptophan-rich region in the transmembrane glycoprotein ectodomain of feline immunodeficiency virus is important for cell entry

ABSTRACT Feline immunodeficiency virus (FIV) provides a valuable animal model by which criteria for lentivirus control strategies can be tested. Previous studies have shown that a 20-mer synthetic peptide of the membrane-proximal ectodomain of FIV transmembrane glycoprotein, designated peptide 59, potently inhibited the growth of tissue culture-adapted FIV in feline fibroblastoid CrFK cells. In the present report we describe the potential of this peptide to inhibit the replication of primary FIV isolates in lymphoid cells. Because antiviral activity of peptide 59 was found to map to a short segment containing three conserved Trp residues, further analyses focused on a derivative of eight amino acids (770W-I777), designated C8. Peptide C8 activity was found to be dependent on conservation of the Trp motif, to be removed from solution by FIV absorbed onto substrate cells, and to be blocked by a peptide derived from the N-terminal portion of FIV transmembrane glycoprotein. Structural studies showed that peptide C8 possesses a conformational propensity highly uncommon for peptides of its size, which may account for its considerable antiviral potency in spite of small size.

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Feline Immunodeficiency Virus Cell Entry

Journal of Virology ◽

10.1128/jvi.75.11.5433-5440.2001 ◽

2001 ◽

Vol 75 (11) ◽

pp. 5433-5440 ◽

Cited By ~ 24

Author(s):

Susan C. S. Frey ◽

Edward A. Hoover ◽

James I. Mullins

Keyword(s):

Virus Replication ◽

Chemokine Receptor ◽

Feline Immunodeficiency Virus ◽

Cell Entry ◽

Cellular Receptor ◽

Circular Dna ◽

Subtype B ◽

Immunodeficiency Virus ◽

Replication Intermediates

ABSTRACT The process of feline immunodeficiency virus (FIV) cell entry was examined using assays for virus replication intermediates. FIV subtype B was found to utilize the chemokine receptor CXCR4, but not CCR5, as a cellular receptor. Zidovudine blocked formation of late viral replication products most effectively, including circular DNA genome intermediates. Our findings extend the role of CXCR4 as a primary receptor for CD4-independent cell entry by FIV.

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Development of Antiviral Fusion Inhibitors: Short Modified Peptides Derived from the Transmembrane Glycoprotein of Feline Immunodeficiency Virus

ChemBioChem ◽

10.1002/cbic.200500390 ◽

2006 ◽

Vol 7 (5) ◽

pp. 774-779 ◽

Cited By ~ 17

Author(s):

Anna Maria D'Ursi ◽

Simone Giannecchini ◽

Cinzia Esposito ◽

Maria Claudia Alcaro ◽

Olimpia Sichi ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Fusion Inhibitors ◽

Transmembrane Glycoprotein ◽

Immunodeficiency Virus ◽

Modified Peptides

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C-Terminal gp40 Peptide Analogs Inhibit Feline Immunodeficiency Virus: Cell Fusion and Virus Spread

Journal of Virology ◽

10.1128/jvi.76.18.9079-9086.2002 ◽

2002 ◽

Vol 76 (18) ◽

pp. 9079-9086 ◽

Cited By ~ 21

Author(s):

R. J. Medinas ◽

D. M. Lambert ◽

W. A. Tompkins

Keyword(s):

Cell Fusion ◽

Feline Immunodeficiency Virus ◽

Synthetic Peptides ◽

Acute Infection ◽

Surface Glycoprotein ◽

Heptad Repeat ◽

Transmembrane Glycoprotein ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1), gp160, is synthesized as a protein precursor that when proteolytically cleaved yields two subunits, gp120 and gp41. gp120 is the surface glycoprotein on HIV-1 responsible for binding to CD4, and gp41 is the transmembrane glycoprotein involved in the membrane fusion process. gp41 is divided into the N-terminal fusion peptide, the heptad repeat 1 (HR1) and HR2 regions, and the C-terminal transmembrane region, which are collectively responsible for virus fusion and entry into the cell. Synthetic peptides derived from the HR2 and HR1 regions of HIV-1LAI have been shown to prevent virus-cell fusion and infection in vitro. In phase II clinical trials in HIV patients, data revealed that T20 has antiviral efficacy and is well tolerated. Similar results were obtained in vitro with HIV-2 and simian immunodeficiency virus, supporting the conservation of the gp41 ectodomain among lentiviruses. Feline immunodeficiency virus (FIV) infection in the cat has been used as a model to develop potential antivirals for HIV. To determine if synthetic gp40 analogs capable of inhibiting FIV infection could be identified, 15 overlapping 35-amino-acid peptides derived from the C-terminal HR2 domain of FIV gp40 were synthesized. These peptides were tested for efficacy against FIV in a syncytium-forming assay with FIV-infected CrFK cells and HeLa cells expressing the FIV receptor CXCR4. Several peptides exhibited activity at the nanogram level. Antiviral activity was confirmed by suppression of reverse transcriptase in a FIV feline CD4+-T-cell (FCD4-E) acute-infection assay. These data demonstrate that synthetic peptides derived from the HR2 domain of the FIV gp41 protein are effective inhibitors of FIV infection.

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Antibodies Generated in Cats by a Lipopeptide Reproducing the Membrane-Proximal External Region of the Feline Immunodeficiency Virus Transmembrane Enhance Virus Infectivity

Clinical and Vaccine Immunology ◽

10.1128/cvi.00140-07 ◽

2007 ◽

Vol 14 (8) ◽

pp. 944-951 ◽

Cited By ~ 8

Author(s):

Simone Giannecchini ◽

Anna Maria D'Ursi ◽

Cinzia Esposito ◽

Mario Scrima ◽

Elisa Zabogli ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Virus Infectivity ◽

Membrane Interface ◽

External Region ◽

Ordered Structures ◽

Membrane Proximal External Region ◽

Transmembrane Glycoprotein ◽

Immunodeficiency Virus ◽

Viable Approach

ABSTRACT The immunogenicity of a lipoylated peptide (lipo-P59) reproducing the membrane-proximal external region (MPER) of the transmembrane glycoprotein of feline immunodeficiency virus (FIV) was investigated with cats. In the attempt to mimic the context in which MPER is located within intact virions, lipo-P59 was administered in association with membrane-like micelles. Analyses showed that in this milieu, lipo-P59 had a remarkable propensity to be positioned at the membrane interface, displayed a large number of ordered structures folded in turn helices, and was as active as lipo-P59 alone at inhibiting FIV infectivity in vitro. The antibodies developed differed from the ones previously obtained by immunizing cats with the nonlipoylated version of the peptide (G. Freer, S. Giannecchini, A. Tissot, M. F. Bachmann, P. Rovero, P. F. Serres, and M. Bendinelli, Virology 322:360-369, 2004) in epitope specificity and in the fact that they bound FIV virions. However, they too lacked virus-neutralizing activity and actually enhanced FIV infectivity for lymphoid cell cultures. It is concluded that the use of MPER-reproducing oligopeptides is not a viable approach for vaccinating against FIV.

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Structural analysis of the principal immunodominant domain of the feline immunodeficiency virus transmembrane glycoprotein.

Journal of Virology ◽

10.1128/jvi.69.4.2110-2118.1995 ◽

1995 ◽

Vol 69 (4) ◽

pp. 2110-2118 ◽

Cited By ~ 27

Author(s):

G Pancino ◽

L Camoin ◽

P Sonigo

Keyword(s):

Structural Analysis ◽

Feline Immunodeficiency Virus ◽

Transmembrane Glycoprotein ◽

Immunodeficiency Virus

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Delayed Infection after Immunization with a Peptide from the Transmembrane Glycoprotein of the Feline Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.72.3.2406-2415.1998 ◽

1998 ◽

Vol 72 (3) ◽

pp. 2406-2415 ◽

Cited By ~ 19

Author(s):

J. Richardson ◽

A. Moraillon ◽

F. Crespeau ◽

S. Baud ◽

P. Sonigo ◽

...

Keyword(s):

Feline Immunodeficiency Virus ◽

Quantitative Assessment ◽

Natural Infection ◽

Acute Infection ◽

Proximal Region ◽

Surface Glycoprotein ◽

Transmembrane Glycoprotein ◽

Delayed Infection ◽

Viral Burden ◽

Immunodeficiency Virus

ABSTRACT Recent advances in the quantitative assessment of viral burden, by permitting the extension of criteria applied to assess the efficacy of vaccines from all-or-none protection to diminution of the viral burden, may allow the identification of original immunogens of value in combined vaccines. Peptides corresponding to three domains of the envelope glycoproteins of feline immunodeficiency virus that are recognized during natural infection were used to immunize cats. After challenge with a primary isolate of feline immunodeficiency virus, the development of acute infection was monitored by quantitative assessment of the viral burden in plasma and tissues by competitive reverse transcription-PCR, by measurement of the humoral response developed to viral components, and by lymphocyte subset analysis. Whereas immunization with two peptides derived from the surface glycoprotein had no effect on the early course of infection, immunization with a peptide derived from the transmembrane glycoprotein delayed infection, as reflected by a diminished viral burden in the early phase of primary infection and delayed seroconversion. This peptide, located in the membrane-proximal region of the extracellular domain, has homology to an epitope of human immunodeficiency virus type 1 recognized by a broadly neutralizing monoclonal antibody. These results suggest that lentivirus transmembrane glycoproteins share a determinant in the juxtamembrane ectodomain which could be of importance in the design of vaccines against AIDS.

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