Probing Sequence Variation in the Receptor-Targeting Domain of Feline Leukemia Virus Envelope Proteins with Peptide Display Libraries

ABSTRACT Determinants of cellular tropism and receptor targeting lie within a short peptide in the Vr1 region of the envelope (Env) proteins of feline leukemia virus (FeLV) subgroups A and C. Libraries of FeLV Env proteins with random amino acid substitutions in the peptide were screened for their ability to deliver a marker gene to D17 and AH927 cells. Screening on D17 canine cells yielded D17-specific Env proteins that used the FeLV-C receptor. Screening on AH927 cells yielded Env proteins with a broader host range, with maximal titers on AH927 cells and similar or lower titers on other cells. These Env proteins used an unidentified non-FeLV receptor for entry. The A5 isolate obtained from the AH927 screen was readily concentrated to yield titers of 105 on human PC-3 prostate tumor cells. The sequence divergence observed among targeting peptides of library-selected Env proteins was greater than that found in parental FeLV isolates. Substitution analyses of a conserved R in the middle of the targeting peptide held constant during screening indicated that maximal titers were obtained only when R was present in both a D17 selected isolate and an AH927 selected isolate. The ability to isolate Env proteins with unique tropisms dependent on the cells on which the library is screened has direct implications for targeting gene delivery vectors.

[1]  J. Margolick,et al.  Improved Coreceptor Usage Prediction and GenotypicMonitoring of R5-to-X4 Transition by Motif Analysis of HumanImmunodeficiency Virus Type 1 env V3 LoopSequences , 2003, Journal of Virology.

[2]  M. Roth,et al.  Targeting a retroviral vector in the absence of a known cell-targeting ligand. , 2003, Human gene therapy.

[3]  M. Roth,et al.  Altering retroviral tropism using a random-display envelope library. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  J. Overbaugh,et al.  Feline Pit2 Functions as a Receptor for Subgroup B Feline Leukemia Viruses , 2001, Journal of Virology.

[5]  M. Alizon,et al.  Cooperation of the V1/V2 and V3 Domains of Human Immunodeficiency Virus Type 1 gp120 for Interaction with the CXCR4 Receptor , 2001, Journal of Virology.

[6]  J Overbaugh,et al.  Cloning of the cellular receptor for feline leukemia virus subgroup C (FeLV-C), a retrovirus that induces red cell aplasia. , 2000, Blood.

[7]  C. Tailor,et al.  A Putative Cell Surface Receptor for Anemia-Inducing Feline Leukemia Virus Subgroup C Is a Member of a Transporter Superfamily , 1999, Journal of Virology.

[8]  M. Essex,et al.  Hypervariable region 3 residues of HIV type 1 gp120 involved in CCR5 coreceptor utilization: therapeutic and prophylactic implications. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Ghosh,et al.  Retrovirus receptor PiT-1 of the Felis catus. , 1998, Biochimica et biophysica acta.

[10]  W. Anderson,et al.  Role of Variable Regions A and B in Receptor Binding Domain of Amphotropic Murine Leukemia Virus Envelope Protein , 1998, Journal of Virology.

[11]  Ying Sun,et al.  A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. , 1998, Science.

[12]  J. Sodroski,et al.  Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody , 1998, Nature.

[13]  M. Essex,et al.  CCR5 coreceptor utilization involves a highly conserved arginine residue of HIV type 1 gp120. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  B. Chesebro,et al.  Selective employment of chemokine receptors as human immunodeficiency virus type 1 coreceptors determined by individual amino acids within the envelope V3 loop , 1997, Journal of virology.

[15]  M. Malim,et al.  HIV‐1 infection of non‐dividing cells: evidence that the amino‐terminal basic region of the viral matrix protein is important for Gag processing but not for post‐entry nuclear import , 1997, The EMBO journal.

[16]  Y Takeuchi,et al.  High-titer packaging cells producing recombinant retroviruses resistant to human serum , 1995, Journal of virology.

[17]  J. Cunningham,et al.  A human amphotropic retrovirus receptor is a second member of the gibbon ape leukemia virus receptor family. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Neil,et al.  Partial dissociation of subgroup C phenotype and in vivo behaviour in feline leukaemia viruses with chimeric envelope genes. , 1992, The Journal of general virology.

[19]  Y Takeuchi,et al.  Feline leukemia virus subgroup B uses the same cell surface receptor as gibbon ape leukemia virus , 1992, Journal of virology.

[20]  R. Weiss,et al.  Receptor interference groups of 20 retroviruses plating on human cells. , 1990, Virology.

[21]  J. Mullins,et al.  Strong sequence conservation among horizontally transmissible, minimally pathogenic feline leukemia viruses , 1988, Journal of virology.

[22]  J. Mullins,et al.  Molecular analysis and pathogenesis of the feline aplastic anemia retrovirus, feline leukemia virus C-Sarma , 1986, Journal of virology.

[23]  J. Mullins,et al.  Nucleotide sequences of a feline leukemia virus subgroup A envelope gene and long terminal repeat and evidence for the recombinational origin of subgroup B viruses , 1986, Journal of virology.

[24]  B. Chesebro,et al.  Different murine cell lines manifest unique patterns of interference to superinfection by murine leukemia viruses. , 1985, Virology.

[25]  A. Rein.  Interference grouping of murine leukemia viruses: a distinct receptor for the MCF-recombinant viruses in mouse cells. , 1982, Virology.

[26]  J. Lechner,et al.  Establishment and characterization of a human prostatic carcinoma cell line (PC-3). , 1979, Investigative urology.

[27]  D. Paulson,et al.  Isolation of a human prostate carcinoma cell line (DU 145) , 1978, International journal of cancer.

[28]  T L Hoffman,et al.  HIV-1 envelope determinants for cell tropism and chemokine receptor use. , 1999, Molecular membrane biology.