Antiviral Activity and Conformational Features of an Octapeptide Derived from the Membrane-Proximal Ectodomain of the Feline Immunodeficiency Virus Transmembrane Glycoprotein

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.

[1]  K. Guthrie,et al.  HIV-1 membrane fusion mechanism: structural studies of the interactions between biologically-active peptides from gp41. , 1996, Biochemistry.

[2]  Richard R. Ernst,et al.  Investigation of exchange processes by two‐dimensional NMR spectroscopy , 1979 .

[3]  K. Wüthrich,et al.  Torsion angle dynamics for NMR structure calculation with the new program DYANA. , 1997, Journal of molecular biology.

[4]  Stuart L. Schreiber,et al.  Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements , 1999, Nature Structural Biology.

[5]  A. Moraillon,et al.  Delayed Infection after Immunization with a Peptide from the Transmembrane Glycoprotein of the Feline Immunodeficiency Virus , 1998, Journal of Virology.

[6]  J. Elder,et al.  Feline immunodeficiency virus as a model for development of molecular approaches to intervention strategies against lentivirus infections. , 1995, Advances in virus research.

[7]  G. Melikyan,et al.  Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion , 2000, The Journal of cell biology.

[8]  S. A. Gallo,et al.  Mode of Action of an Antiviral Peptide from HIV-1 , 2001, The Journal of Biological Chemistry.

[9]  J. Sodroski,et al.  The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. , 1998, Science.

[10]  A. Motta,et al.  Viscosity as a conformational sieve. NOE of linear peptides in cryoprotective mixtures , 1991 .

[11]  P. S. Kim,et al.  HIV Entry and Its Inhibition , 1998, Cell.

[12]  E. Hunter,et al.  A Conserved Tryptophan-Rich Motif in the Membrane-Proximal Region of the Human Immunodeficiency Virus Type 1 gp41 Ectodomain Is Important for Env-Mediated Fusion and Virus Infectivity , 1999, Journal of Virology.

[13]  Christos,et al.  Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: implications for the viral fusion mechanism. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Malim,et al.  Workshop Summary: Lessons from the Cat: Feline Immunodeficiency Virus as a Tool to Develop Intervention Strategies against Human Immunodeficiency Virus Type 1 , 1998 .

[15]  G. Petsko,et al.  Proteins at work: "stop-action" pictures at subzero temperatures. , 1984, Advances in protein chemistry.

[16]  J. Overbaugh,et al.  Receptors and Entry Cofactors for Retroviruses Include Single and Multiple Transmembrane-Spanning Proteins as well as Newly Described Glycophosphatidylinositol-Anchored and Secreted Proteins , 2001, Microbiology and Molecular Biology Reviews.

[17]  A. Agirre,et al.  Membrane Interface-Interacting Sequences within the Ectodomain of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein: Putative Role during Viral Fusion , 2000, Journal of Virology.

[18]  G. Shaw,et al.  Sensitivity of Human Immunodeficiency Virus Type 1 to Fusion Inhibitors Targeted to the gp41 First Heptad Repeat Involves Distinct Regions of gp41 and Is Consistently Modulated by gp120 Interactions with the Coreceptor , 2001, Journal of Virology.

[19]  B. Fehse,et al.  Membrane-Anchored Peptide Inhibits Human Immunodeficiency Virus Entry , 2001, Journal of Virology.

[20]  J. Kappes,et al.  Sensitivity of Human Immunodeficiency Virus Type 1 to the Fusion Inhibitor T-20 Is Modulated by Coreceptor Specificity Defined by the V3 Loop of gp120 , 2000, Journal of Virology.

[21]  J. Schneider-Mergener,et al.  Shared Usage of the Chemokine Receptor CXCR4 by Primary and Laboratory-Adapted Strains of Feline Immunodeficiency Virus , 1999, Journal of Virology.

[22]  J. Mullins,et al.  Feline Immunodeficiency Virus Cell Entry , 2001, Journal of Virology.

[23]  N. Pedersen,et al.  Nucleotide sequence and genomic organization of feline immunodeficiency virus. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Bendinelli,et al.  Inhibition of feline immunodeficiency virus infection in vitro by envelope glycoprotein synthetic peptides. , 1996, Virology.

[25]  Paul W. H. I. Parren,et al.  Broadly Neutralizing Antibodies Targeted to the Membrane-Proximal External Region of Human Immunodeficiency Virus Type 1 Glycoprotein gp41 , 2001, Journal of Virology.

[26]  P S Kim,et al.  Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Marian C. Horzinek,et al.  Antibody response in cats to the envelope proteins of feline immunodeficiency virus: identification of an immunodominant neutralization domain. , 1994, Virology.

[28]  M. Bendinelli,et al.  The antiviral activity of a synthetic peptide derived from the envelope SU glycoprotein of feline immunodeficiency virus maps in correspondence of an amphipathic helical segment. , 1998, Biochemical and biophysical research communications.

[29]  Michael S. Kay,et al.  Protein Design of an HIV-1 Entry Inhibitor , 2001, Science.

[30]  Eric Hunter,et al.  Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry , 1998, Nature Medicine.

[31]  P. S. Kim,et al.  Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[33]  J. Elder,et al.  Binding of Recombinant Feline Immunodeficiency Virus Surface Glycoprotein to Feline Cells: Role of CXCR4, Cell-Surface Heparans, and an Unidentified Non-CXCR4 Receptor , 2001, Journal of Virology.

[34]  Ad Bax,et al.  MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy , 1985 .

[35]  John P. Moore,et al.  Genetic Subtypes, Humoral Immunity, and Human Immunodeficiency Virus Type 1 Vaccine Development , 2001, Journal of Virology.

[36]  Y. Lu,et al.  Epitope-vaccine as a new strategy against HIV-1 mutation. , 2001, Immunology letters.

[37]  Q. Sattentau,et al.  Inactivation of Human Immunodeficiency Virus Type 1 Infectivity with Preservation of Conformational and Functional Integrity of Virion Surface Proteins , 1998, Journal of Virology.

[38]  Y. G. Yu,et al.  Design of a peptide inhibitor that blocks the cell fusion mediated by glycoprotein 41 of human immunodeficiency virus type 1. , 2000, AIDS research and human retroviruses.

[39]  M. Bendinelli,et al.  Most potential linear B cell epitopes of Env glycoproteins of feline immunodeficiency virus are immunogenically silent in infected cats. , 1997, AIDS research and human retroviruses.

[40]  M. Pistello,et al.  Autologous and Heterologous Neutralization Analyses of Primary Feline Immunodeficiency Virus Isolates , 1998, Journal of Virology.

[41]  C. E. Parker,et al.  Fine Definition of the Epitope on the gp41 Glycoprotein of Human Immunodeficiency Virus Type 1 for the Neutralizing Monoclonal Antibody 2F5 , 2001, Journal of Virology.

[42]  A. Debnath,et al.  A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody. , 1999, Journal of virological methods.

[43]  E. Holmes,et al.  Evolution of structural proteins of feline immunodeficiency virus: molecular epidemiology and evidence of selection for change. , 1993, The Journal of general virology.

[44]  Deborah Fass,et al.  Core Structure of gp41 from the HIV Envelope Glycoprotein , 1997, Cell.

[45]  R. Blumenthal,et al.  Role of the Membrane-Proximal Domain in the Initial Stages of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein-Mediated Membrane Fusion , 1999, Journal of Virology.

[46]  Richard R. Ernst,et al.  Multiple quantum filters for elucidating NMR coupling networks , 1982 .

[47]  Min Lu,et al.  Structural and Functional Analysis of Interhelical Interactions in the Human Immunodeficiency Virus Type 1 gp41 Envelope Glycoprotein by Alanine-Scanning Mutagenesis , 2001, Journal of Virology.

[48]  L. Picard,et al.  Shared usage of the chemokine receptor CXCR4 by the feline and human immunodeficiency viruses , 1997, Journal of virology.

[49]  M. Bendinelli,et al.  Serum neutralization of feline immunodeficiency virus is markedly dependent on passage history of the virus and host system , 1994, Journal of virology.

[50]  T. Matthews,et al.  The inhibitory activity of an HIV type 1 peptide correlates with its ability to interact with a leucine zipper structure. , 1995, AIDS research and human retroviruses.

[51]  J. Lifson,et al.  Chemical inactivation of retroviral infectivity by targeting nucleocapsid protein zinc fingers: a candidate SIV vaccine. , 1998, AIDS research and human retroviruses.

[52]  E. De Clercq,et al.  Bicyclams, Selective Antagonists of the Human Chemokine Receptor CXCR4, Potently Inhibit Feline Immunodeficiency Virus Replication , 1999, Journal of Virology.

[53]  T. Matthews,et al.  Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[54]  M Pistello,et al.  Feline immunodeficiency virus: an interesting model for AIDS studies and an important cat pathogen , 1995, Clinical microbiology reviews.

[55]  C. Chappey,et al.  Structure and variations of feline immunodeficiency virus envelope glycoproteins. , 1993, Virology.

[56]  Min Lu,et al.  Inhibition of Human Immunodeficiency Virus Type 1 Infectivity by the gp41 Core: Role of a Conserved Hydrophobic Cavity in Membrane Fusion , 1999, Journal of Virology.

[57]  L. Camoin,et al.  Structural analysis of the principal immunodominant domain of the feline immunodeficiency virus transmembrane glycoprotein , 1995, Journal of virology.

[58]  P S Kim,et al.  Crystal structure of the simian immunodeficiency virus (SIV) gp41 core: conserved helical interactions underlie the broad inhibitory activity of gp41 peptides. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[59]  N. Pedersen,et al.  Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. , 1987, Science.

[60]  D. Bolognesi,et al.  A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion , 1995, Journal of virology.

[61]  A. Moraillon,et al.  Neutralization sensitivity and accessibility of continuous B cell epitopes of the feline immunodeficiency virus envelope. , 1996, The Journal of general virology.

[62]  J. N. Flynn,et al.  FIV infection of the domestic cat: an animal model for AIDS. , 1997, Immunology today.

[63]  R. Munn,et al.  Development of IL-2-independent feline lymphoid cell lines chronically infected with feline immunodeficiency virus: importance for diagnostic reagents and vaccines. , 1991, Intervirology.

[64]  T. Matthews,et al.  Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides , 1998, Journal of Virology.

[65]  S. Durell,et al.  Dilation of the Human Immunodeficiency Virus–1 Envelope Glycoprotein Fusion Pore Revealed by the Inhibitory Action of a Synthetic Peptide from gp41 , 1998, The Journal of cell biology.

[66]  M. Pistello,et al.  AIDS Vaccination Studies Using an Ex Vivo Feline Immunodeficiency Virus Model: Failure To Protect and Possible Enhancement of Challenge Infection by Four Cell-Based Vaccines Prepared with Autologous Lymphoblasts , 2002, Journal of Virology.

[67]  P. S. Kim,et al.  Inhibiting HIV-1 Entry Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket , 1999, Cell.

[68]  S. Hammer,et al.  HIV fusion and its inhibition. , 2001, Antiviral research.

[69]  Molecular mimicry between the trimeric ectodomain of the transmembrane protein of immunosuppressive lentiviruses (HIV-SIV-FIV) and interleukin 2. , 2000, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[70]  Shibo Jiang,et al.  HIV-1 inhibition by a peptide , 1993, Nature.