The feline leukaemia virus (FeLV) is a gamma-retrovirus commonly affecting cats. Infection with this virus often leads to fatal outcomes and, so far, no cure is available for this disease. Synthetic peptides with structures mimicking the transmembrane protein of the viral surface proteins hold the potential to effectively interfere with viral entry by hampering the fusion of viral and host cell membranes and constitute a novel approach for the treatment of infections with retroviruses. We identified and synthetically produced 11 FeLV peptides and evaluated their potential to block FeLV infection in vitro.
Methods
Cell cultures were exposed to FeLV subgroup A prior to the addition of the peptides. The inhibitory effect of the peptides was assessed by measuring FeLV gag protein in the supernatant of peptide versus mock-treated cell cultures using an ELISA.
Results
A peptide (EPK364) of 37 amino acids in length, with sequence homology to the HIV fusion inhibitor T-20, significantly suppressed viral replication by 88%, whereas no effects were found for shorter peptides. Two structurally modified variants of EPK364 also inhibited viral replication by up to 58% (EPK397) and 27% (EPK398).
Conclusions
Our data support the identification of synthetic FeLV peptides that have the potential for a curative short-term therapy of viraemic cats. In addition, these peptides might become an important tool in xenotrans-plantation, where endogenous gammaretroviruses of the donor species might be able to infect the host.
GulickR.M., MellorsJ.W., HavlirD.Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med1997; 337: 734–739.
12.
KoelschK.K., CooperD.A.Integrase inhibitors in salvage therapy regimens for HIV-1 infection. Curr Opin HIV AIDS2009; 4: 518–523.
13.
WildC.T., ShugarsD.C., GreenwellT.K., McDanalC.B., MatthewsT.J.Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A1994; 91: 9770–9774.
14.
JiangS., LinK., StrickN., NeurathA.R.HIV-1 inhibition by a peptide. Nature1993; 365: 113.
15.
GiannecchiniS., Di FenzaA., D'UrsiA.M.Antiviral activity and conformational features of an octapeptide derived from the membrane-proximal ectodomain of the feline immunodeficiency virus transmembrane glycoprotein. J Virol2003; 77: 3724–3733.
16.
ChanD.C., KimP.S.HIV entry and its inhibition. Cell1998; 93: 681–684.
17.
EckertD.M., KimP.S.Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region. Proc Natl Acad Sci U S A2001; 98: 11187–11192.
18.
ChanD.C., FassD., BergerJ.M., KimP.S.Core structure of gp41 from the HIV envelope glycoprotein. Cell1997; 89: 263–273.
19.
EckertD.M., KimP.S.Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem2001; 70: 777–810.
20.
LombardiS., MassiC., IndinoE.Inhibition of feline immunodeficiency virus infection in vitro by envelope glycoprotein synthetic peptides. Virology1996; 220: 274–284.
21.
WildC., GreenwellT., MatthewsT.A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res Hum Retroviruses1993; 9: 1051–1053.
22.
OuW., SilverJ.Inhibition of murine leukemia virus envelope protein (env) processing by intracellular expression of the env N-terminal heptad repeat region. J Virol2005; 79: 4782–4792.
23.
WallinM., EkstromM., GaroffH.Receptor-triggered but alkylation-arrested env of murine leukemia virus reveals the transmembrane subunit in a prehairpin conformation. J Virol2006; 80: 9921–9925.
24.
HeY., XiaoY., SongH.Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J Biol Chem2008; 283: 11126–11134.
25.
KilbyJ.M., HopkinsS., VenettaT.M.Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med1998; 4: 1302–1307.
26.
MoltóJ., RuizL., ValleM.Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Antivir Ther2006; 11: 47–51.
27.
LutzH., PedersenN.C., DurbinR., TheilenG.H.Monoclonal antibodies to three epitopic regions of feline leukemia virus p27 and their use in enzyme-linked immunosorbent assay of p27. J Immunol Methods1983; 56: 209–220.
28.
Hofmann-LehmannR., HuderJ.B., GruberS.Feline leukaemia provirus load during the course of experimental infection and in naturally infected cats. J Gen Virol2001; 82: 1589–1596.
29.
HrinR., MontgomeryD.L., WangF.Short communication: in vitro synergy between peptides or neutralizing antibodies targeting the N- and C-terminal heptad repeats of HIV Type 1 gp41. AIDS Res Hum Retroviruses2008; 24: 1537–1544.
30.
MizukoshiF., BabaK., GotoY.Antiviral activity of membrane fusion inhibitors that target gp40 of the feline immunodeficiency virus envelope protein. Vet Microbiol2009; 136: 155–159.
31.
WeissR.A.Transgenic pigs and virus adaptation. Nature1998; 391: 327–328.
32.
OtakaA., NakamuraM., NamekiD.Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angew Chem Int Ed Engl2002; 41: 2937–2940.
