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Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry

Abstract

T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT–PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.

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Figure 1: Proposed mechanism of T-20 action.
Figure 2: Median plasma viral load changes from baseline for subjects in all four dose groups: Filled circle, 3 mg; open triangle, 10 mg; filled square, 30 mg; open diamond, 100 mg.
Figure 3: Plasma viral load changes from baseline for the four subjects in the 100-mg dose group (P < 0.

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References

  1. Carpenter, C.C. et al. Anti-retroviral therapy for HIV infection in 1998. J. Am. Med. Assoc. 280, 78–86 (1998).

    Article  CAS  Google Scholar 

  2. Eron, J.J. et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N. Engl. J. Med. 333, 1662–9 ( 1995).

    Article  CAS  Google Scholar 

  3. Markowitz, M. et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N. Engl. J. Med. 333, 1534–9 (1995).

    Article  CAS  Google Scholar 

  4. Hammer, S. et al. A randomized, placebo-controlled trial of indinavir in combination with two nucleoside analogs in HIV-infected persons with CD4 cell counts less than or equal to 200 per cubic millimeter. N. Engl. J. Med. 337, 725 (1997).

    Article  CAS  Google Scholar 

  5. Saag, M.S. Nucleoside analogs: adverse effects. Hosp. Pract. 27 (supp), 26-36 (1992).

  6. McDonald, C.K. & Kuritzkes, D.R. HIV-1 protease inhibitors. Arch. Intern. Med. 157, 951–959 (1997).

    Article  CAS  Google Scholar 

  7. Richman, D.D. Resistance of clinical isolates of HIV to anti-retroviral agents. Antimicrob. Agents Chemother. 37, 1207– 1213 (1993).

    Article  CAS  Google Scholar 

  8. Condra, J.H. et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374, 569– 71 (1995).

    Article  CAS  Google Scholar 

  9. Kwong, P.D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 ( 1998).

    Article  CAS  Google Scholar 

  10. Chan, D.C., Fass, D., Berger, J.M. & Kim, P.S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263–73 (1997).

    Article  CAS  Google Scholar 

  11. Gallaher, W., Ball, J., Garry, R., Griffin, M. & Montelaro R. A general model of the transmembrane proteins of HIV and other retroviruses. AIDS Res. Hum. Retroviruses 5, 431–40 (1989).

    Article  CAS  Google Scholar 

  12. Delwart, E., Mosialos, G. & Gilmore, T. Retroviral envelope glycoproteins contain a "leucine zipper"-like repeat. AIDS Res. Hum. Retroviruses 6, 703–6 (1989).

    Article  Google Scholar 

  13. Chen, C.H., Matthews, T., McDanal, C., Bolognesi, D. & Greenberg M. A molecular clasp in HIV-1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion. J. Virol. 69, 3771–7 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lawless, M.K. et al. HIV-1 membrane fusion mechanism: structural studies of the interactions between biologically-active peptides from gp41. Biochemistry 35, 13697–708 ( 1996).

    Article  CAS  Google Scholar 

  15. Matthews, T. et al. Structural rearrangements in the transmembrane glycoprotein after receptor binding. Immunol. Rev. 140, 93–104 (1994).

    Article  CAS  Google Scholar 

  16. Wild, C., Greenwell, T., Shugars, D., Rimsky-Clarke & Matthews T. The inhibitory activity of an HIV-1 peptide correlates with its ability to interact with a leucine zipper structure. AIDS Res. Hum. Retroviruses 11, 323–5 (1995).

    Article  CAS  Google Scholar 

  17. Wild C., Oas T., McDanal C., Bolognesi D. & Matthews T. A synthetic peptide inhibitor of HIV replication: correlation between solution structure and viral inhibition. Proc. Natl. Acad. Sci. USA 89, 10537–41 ( 1992).

    Article  CAS  Google Scholar 

  18. Tan, K., Liu, J.H., Want, J.H., Shen, S., & Lu, M. Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc. Natl. Acad. Sci. USA 94, 12303–308 (1997).

    Article  CAS  Google Scholar 

  19. Weissenhorn, W.A., Dessen, A., Harrison, S.C., Skehel, J.J. & Wiley, D.C. Atomic structure of the ectodomain from HIV-1 gp41. Nature 387, 426– 30 (1997).

    Article  CAS  Google Scholar 

  20. Dubay, J., Roberts, S., Brody, B. & Hunter, E. Mutations in the leucine zipper of HIV-1 transmembrane glycoprotein affect fusion and infectivity. J. Virol. 66, 4748–56 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wild, C. et al. Propensity for a leucine zipper-like domain of HIV-1 gp41 to form oligomers correlates with a role in virus-induced fusion rather than assembly of the glycoprotein complex. Proc. Natl. Acad. Sci. USA 91, 12676–80 ( 1994).

    Article  CAS  Google Scholar 

  22. Bullough, P.A., Hughson, M., Skehel, J.J. & Wiley, D.C. Structure of influena haemagglutinin at the pH of membrane fusion. J. Virol. 371, 37–43 ( 1994).

    CAS  Google Scholar 

  23. Carr, C. & Kim, P.S. A spring-loaded mechanism for the conformational change of influenza hemaglutinin. Cell 73, 823–32 (1993).

    Article  CAS  Google Scholar 

  24. Wild, C., Greenwell, T. & Matthews, T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res. Hum. Retroviruses 9, 1051–3 (letter) ( 1993).

    Article  CAS  Google Scholar 

  25. Wild, C.T., Shugars, D.C., Greenwell, T.K., McDanal, C.B. & Matthews, T.J. Peptides corresponding to a predictive alpha-helical domain of HIV-1 gp41 are potent inhibitors of virus infection. Proc. Natl. Acad. Sci. USA 91, 9770– 4 (1994).

    Article  CAS  Google Scholar 

  26. Rimsky, L.T., Shugars, D.C. & Matthews, T. Determinants of HIV-1 resistance to gp41-derived inhibitory peptides. J. Virol. 72, 986– 992 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wei, X, et al. Viral dynamics in HIV-1 infection. Nature 373, 117–22 (1995).

    Article  CAS  Google Scholar 

  28. Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123– 26 (1995).

    Article  CAS  Google Scholar 

  29. Herz, A.V.M., Bonhoeffer, S., Anderson, R.M., May, R.M. & Nowak, M.A. Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay. Proc. Natl. Acad. Sci. USA 93, 7247–51 (1996).

    Article  CAS  Google Scholar 

  30. Perelson, A.S., Neumann, A.U., Markowitz, M., Leonard, J.M. & Ho, D.D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582–86 ( 1996).

    Article  CAS  Google Scholar 

  31. Montaner, J.S.G. et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. J. Am. Med. Assoc. 279, 930–37 (1998).

    Article  CAS  Google Scholar 

  32. Nowak, M.A., Bonhoeffer, S., Shaw, G.M. & May, R.M. Anti-viral drug treatment: dynamics of resistance in free virus and infected cell populations. J. Theor. Biol. 184, 203 –17 (1997).

    Article  CAS  Google Scholar 

  33. Bonhoeffer, S., May, R.M., Shaw, G.M. & Nowak, M.A. Virus dynamics and drug treatment. Proc. Natl. Acad. Sci. USA 94, 6971–76 (1997).

    Article  CAS  Google Scholar 

  34. Perelson, A.S. et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 387, 188–191 (1997).

    Article  CAS  Google Scholar 

  35. Baba, M. et al. Mechanism of inhibitory effect of dextran sulfate and heparin on replication of HIV in vitro. Proc. Natl. Acad. Sci. USA 85, 6132–36 (1988).

    Article  CAS  Google Scholar 

  36. Mitsuya, H. et al. Dextran sulfate suppression of viruses in the HIV family: inhibition of virion binding to CD4+ cells. Science 240, 646–48 (1988).

    Article  CAS  Google Scholar 

  37. Flexner, C. et al. Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in HIV infection. Antimicrob. Agents Chemother. 35, 2544–50 (1991).

    Article  CAS  Google Scholar 

  38. Fisher, R.A. et al. HIV infection is blocked in vitro by recombinant soluble CD4. Nature 331, 76–78 (1988).

    Article  CAS  Google Scholar 

  39. Schooley, R.T. et al. Recombinant soluble CD4 therapy in patients with AIDS and AIDS-related complex. Ann. Intern. Med. 112, 247–53 (1990).

    Article  CAS  Google Scholar 

  40. Meng, T.C. et al. Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 8, 152–160 (1995).

    Article  CAS  Google Scholar 

  41. Shacker, T. et al. Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 9145–152 ( 1995).

  42. Chen, J.D., Bai, X., Yang, A.G., Cong, Y. & Chen, S.Y. Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy. Nature Med. 3, 1110–1116 (1997).

    Article  CAS  Google Scholar 

  43. Donzella, G.A. et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Med. 4, 72– 77 (1998).

    Article  CAS  Google Scholar 

  44. Zinman, B., Tildesley, H., Chiasson, J.L., Tsui, E. & Strack, T. Insulin Lispro in CSII: results of a double-blind crossover study. Diabetes 46, 44043 (1997).

    Article  Google Scholar 

  45. Pachl, C. et al. Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay . J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 8, 446–54 (1995).

    Article  CAS  Google Scholar 

  46. Cao, Y. et al. Clinical evaluation of branched DNA signal amplification for quantifying HIV type 1 in human plasma. AIDS Res. Hum. Retroviruses 11, 353–61 (1995).

    Article  CAS  Google Scholar 

  47. Schockmel, G.A., Yerly, S. & Perrin, L. Detection of low HIV-1 levels in plasma. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 14, 179 –83 (1997).

    Article  CAS  Google Scholar 

  48. SAS/STAT User's Guide Version 6, 4th edn., Vol. 1 & 2 (SAS Institute, Cary, North Carolina, 1989 ).

  49. Chan, D. C. and Kim P. S. HIV Entry and Its Inhibition. Cell 93, 681–84 ( 1998).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the study participants; R.P. Bucy for advice and assistance with figures; and Y. Niu for technical assistance. This study was supported by grants from Trimeris, the UAB Center for AIDS Research (NIH P30 A127767), and the UAB General Clinical Research Center (NCRR M01 RR00032). E.H., D.B. and T.M. own stock in Trimeris, have served on the Board of Directors and are consultants for the company; M.S.S. is a consultant for the company.

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Kilby, J., Hopkins, S., Venetta, T. et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 4, 1302–1307 (1998). https://doi.org/10.1038/3293

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