Recent observations indicated that several porphyrins bound to the V3 loop of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1 (HIV-1) and inhibited infection of cells by HIV-1. The tin derivative of protoporphyrin IX (Sn-PTP-IX) has already been used clinically in humans to suppress hyperbilirubinemia. It was therefore of interest to determine whether Sn-PTP-IX has anti-HIV-1 activity. It is demonstrated here that Sn-PTP-IX effectively inhibited infection by several HIV-1 isolates (HIB, MN, RF, SF-2 and two isolates resistant to azidothymidine). This was surprising, since earlier studies indicated that incorporation of other metals into porphyrins markedly decreased their antiviral activity. Sn-PTP-IX blocked the binding to gp120 of anti-V3-loop-specific antibodies and of monoclonal antibodies specific for the CD4 binding site on gp120. The latter effect appeared to be allosteric and was not observed with a deletion mutant of gp 120 lacking the V3 loop sequence. This suggests that Sn-PTP-IX binds to the V3 loop and distorts the native conformation of the HIV-1 envelope, thereby preventing infection. These results merit the consideration of Sn-PTP-IX as a prophylactic and chemotherapeutic agent against HIV-1.
References
1.
AndersonK.E.SimionattoC.S.DrummondG.S., and KappasA. (1986) Disposition of tin-protoporphyrin and suppression of hyperbilirubinemia in humans. Clin Pharmacol Ther39: 510–520.
2.
AsanakaM.KurimuraT.ToyaH.OgakiJ., and KatoY. (1989) Anti-HIV activity of protoporphyrin. AIDS3: 403–404.
3.
BerglundL.AngelinB.BlomstrandR.DrummondG., and KappasA. (1988) Sn-protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase activity in normal human subjects. Hepatology8: 625–631.
4.
BreslowE.ChandraR., and KappasA. (1986) Biochemical properties of the heme oxygenase inhibitor, Sn-protoporphyrin. Interactions with apomyoglobin and human serum albumin. J Biol Chem261: 3135–3141.
5.
DaileyH.A.JonesO.S., and KarrS.W. (1989) Interaction of free porphyrins and metalloporphyrins with mouse ferrochelatase. A model for the active site of ferrochelatase. Biochim Biophys Acta999: 7–11.
6.
DeCampD.L.BabéL.M.SaltoR.LucichJ.L.KooM.-S.KahlS.B., and CraikC.S. (1992) Specific inhibition of HIV-1 protease by boronated porphyrins. J Med Chem35: 3426–3428.
7.
DixonD.W.SchinaziR., and MarzilliL.G. (1990) Porphyrins as agents against the human immunodeficiency virus. Ann NY Acad Sci616: 511–513.
8.
DixonD.W.KimM.S.KumarV.ObaraG.MarzilliL.G., and SchinaziR.F. (1992) Amino- and hydroxytetraphenyl-porphyrins with activity against the human immunodeficiency virus. Antiviral Chem Chemother3: 279–282.
9.
DrummondG.S., and KappasA. (1981) Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc Natl Acad Sci USA78: 6466–6470.
10.
D'SouzaM.P.DurdaP.HansonC.V., and MilmanG. (1991) Evaluation of monoclonal antibodies to HIV-1 by neutralization and serological assays: an international collaboration. AIDS5: 1061–1070.
11.
EmtestamL.BerglundL.AngelinB.DrummondG.S., and KappasA. (1989) Tin-protoporphyrin and long wave length ultraviolet light in treatment of psoriasis. Lanceti: 1231–1233.
12.
EmtestamL.AngelinB.BerglundL.DrummondG.S., and KappasA. (1993) Photodynamic properties of Sn-protoporphyrin: Clinical investigations and phototesting in human subjects. Acta Derm Venereol (Stockh)73: 26–30.
13.
FuhrhopJ.-H., and LumbantobingT. (1970) The redox properties of tin (IV) and germanium (IV)-octaethyl porphinatodihydroxides as compared to other metallo-octaethylporphins. Tetrahedron Letters32: 2815–2818.
14.
GalbraithR.A., and KappasA. (1989) Pharmacokinetics of tin-mesoporphyrin in man and the effects of tin-chelated porphyrins on hyperexcretion of heme pathway precursors in patients with acute inducible porphyria. Hepatology9: 882–888.
15.
KappasA., and DrummondG.S. (1986) Control of heme metabolism with synthetic metalloporphyrins. J Clin Invest77: 335–339.
16.
KappasA.DrummondG.S.SimionattoC.S., and AndersonK.E. (1984) Control of heme oxygenase and plasma levels of bilirubin by a synthetic heme analogue, tin-protoporphyrin. Hepatology4: 336–341.
17.
KappasA.DrummondG.S.ManolaT.PetmezakiS., and ValaesT. (1988) Sn-protoporphyrin use in the management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO incompatibility. Pediatrics81: 485–497.
18.
KeinoH.MimuraS.NagaeH.BannoT., and KashiwamataS. (1993) Protection by L-ascorbic acid against phototoxicity in tin-protoporphyrin-treated suckling rats. Biol Neonate63: 183–190.
19.
LaalS., and Zolla-PaznerS. (1993) Epitopes of HIV-1 glycoproteins recognized by the human immune system. In Immunochemistry of AIDS, Chemical Immunology, Vol. 56. NorrbyE. (ed.). Basel: Karger, pp. 91–111.
20.
LamanJ.D.SchellekensM.M.LewisG.K.MooreJ.P.MatthewsT.J.LangedijkJ.P.M.MeloenR.H.BoersmaW.J.A., and ClaasenE. (1993) A hidden region in the third variable domain of HIV-1 NIB gp120 identified by a monoclonal antibody. AIDS Res Hum Retroviruses9: 605–612.
21.
LevereR.D.GongY.-F.KappasA.BucherD.J.WormserG.P., and AbrahamN.G. (1991) Heme inhibits human immunodeficiency virus 1 replication in cell cultures and enhances the antiviral effect of zidovudine. Proc Natl Acad Sci USA88: 1756–1759.
22.
MainesM.D., and TrakshelG.M. (1992) Tin-protoporphyrin: A potent inhibitor of hemoprotein-dependent steroidogenesis in rat adrenals and testes. J Pharmacol Exp Ther260: 909–916.
23.
MarkJ.A., and MainesM.D. (1992) Tin-protoporphyrin-mediated disruption in vitro of heme oxygenase-2 protein integrity and activity in rat brain. Pediatric Research32: 324–329.
24.
MooreJ.P.ThaliM.JamesonB.A.VignauxF.LewisG.K.PoonS.-W.CharlesM.FungM.S.SunB.DurdaP.J.ÅkerblomL.WahrenB.HoD.D.SattentauQ.J., and SodroskiJ. (1993) Immunochemical analysis of the gp120 surface glycoprotein of human immunodeficiency virus type 1 : Probing the structure of the C4 and V4 domains and the interaction of the C4 domain with the V3 loop. J Virol67: 4785–4796.
25.
MorrisonH.G.KirchhoffF., and DesrosiersR.C. (1993) Evidence for the cooperation of gp120 amino acids 322 and 448 in SIVmac entry. Virology195: 167–174.
26.
NaraP.L.SmitL.DunlopN.HatchW.MergesM.WatersD.KelliherJ.GalloR.C.FischingerP.J., and GoudsmitJ. (1990) Emergence of viruses resistant to neutralization by V3-specific antibodies in experimental human immunodeficiency virus type 1 HIB infection of chimpanzees. J Virol64: 3779–3791.
27.
NeurathA.R. (1993) B cell antigenic site mapping of HIV-1 glycoproteins. In Immunochemistry of AIDS, Chemical Immunology, Vol. 56. NorrbyE. (ed.). Basel: Karger, pp. 34–60.
28.
NeurathA.R.StrickN., and JiangS. (1993) Rapid prescreening for antiviral agents against HIV-1 based on their inhibitory activity in site-directed immunoassays. Approaches applicable to epidemic HIV-1 strains. Antiviral Chem Chemother4: 207–214.
29.
NeurathA.R.HaberfieldP.JoshiB.HewlettI.K.StrickN., and JiangS. (1991a) Rapid prescreening for antiviral agents against HIV-1 based on their inhibitory activity in site-directed immunoassays I. The V3 loop of gp120 as target. Antiviral Chem Chemother2: 303–312.
30.
NeurathA.R.JiangS.StrickN.KolbeH.KienyM.-P.MuchmoreE., and GirardM. (1991b) Antibody responses of chimpanzees immunized with synthetic peptides corresponding to full length V3 hypervariable loops of HIV-1 envelope glycoproteins gp120. AIDS Res Hum Retroviruses7: 813–823.
31.
NeurathA.R.StrickN.HaberfieldP., and JiangS. (1992a) Rapid prescreening for antiviral agents against HIV-1 based on their inhibitory activity in site-directed immunoassays. II. Porphyrins reacting with the V3 loop of gp120. Antiviral Chem Chemother3: 55–63.
32.
NeurathA.R.StrickN., and JiangS. (1992b) Synthetic peptides and anti-peptide antibodies as probes to study interdo-main interactions involved in virus assembly: The envelope of the human immunodeficiency virus (HIV-1). Virology188: 1–13.
33.
NovogrodskyA.SuthanthiranM., and StenzelK.H. (1989) immune stimulatory properties of metalloporphyrins. J Immunol143: 3981–3987.
34.
PinterA.HonneW.J., and TilleyS.A. (1993) Conformational changes affecting the V3 and CD4-binding domains of human immunodeficiency virus type 1 gp120 associated with env processing and with binding of ligands to these sites. J Virol67: 5692–5697.
35.
PollardS.R.RosaM.D.RosaJ.J., and WileyD.C. (1992) Truncated variants of gp120 bind CD4 with high affinity and suggest a minimum CD4 binding region. EMBO J11: 585–591.
36.
StamatatosL., and Cheng-MayerC. (1993) Evidence that the structural conformation of envelope gp120 affects human immunodeficiency virus type 1 infectivity, host range, and syncytium-forming ability. J Virol67: 5635–5639.
37.
StevensonD.K.RodgersP.A., and VremanH.J. (1989) The use of metalloporphyrins for the chemoprevention of neonatal jaundice. Am J Dis Child143: 353–356.
38.
ThaliM.OlshevskyU.FurmanC.GabuzdaD.PosnerM., and SodroskiJ. (1991) Characterization of a discontinuous human immunodeficiency virus type 1 gp120 epitope recognized by a broadly reactive neutralizing human monoclonal antibody. J Virol65: 6188–6193.
39.
TrakshelG.M.SlussP.M., and MainesM.D. (1992) Comparative effects of tin- and zinc-protoporphyrin on steroidogenesis: Tin-protoporphyrin is a potent inhibitor of cytochrome P-450-dependent activities in the rat adrenals. Pediatric Research31: 196–201.
40.
WeissG.LuttonJ.D.FuchsD.Werner-FelmayerG.BockG.AbrahamN.G.KappasA.LevereR.D., and WachterH. (1993) Comparative effects of heme arid metalloporphyrins on interferon-gamma-mediated pathways in monocytic cells (THP-1). Proc Soc Exp Biol Med202: 470–475.
41.
WilleyR.L., and MartinM.A. (1993) Association of human immunodeficiency virus type 1 envelope glycoprotein with particles depends on interactions between the third variable and conserved regions of gp120. J Virol67: 3639–3643.
42.
WyattR.ThaliM.TilleyS.PinterA.PosnerM.HoD.RobinsonJ., and SodroskiJ. (1992) Relationship of the human immunodeficiency virus type 1 gp120 third variable loop to a component of the CD4 binding site in the fourth conserved region. J Virol66: 6997–7004.
43.
WyattR.SullivanN.ThaliM.RepkeH.HoD.RobinsonJ.PosnerM., and SodroskiJ. (1993) Functional and immunologic characterization of human immunodeficiency virus type 1 envelope glycoproteins containing deletions of the major variable regions. J Virol67: 4557–4565.
