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Bovine β–lactoglobulin modified by 3–hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV

Abstract

Sexual transmission is the most frequent (86%) route of adult HIV–1 transmission worldwide1. In the absence of a prophylactic anti–HIV vaccine, other methods of preventing infection should be implemented. Virucidal spermicides have been considered for this purpose, but their application is contraindicated by adverse effects2. Anti–HIV drugs3 or virus–neutralizing monoclonal antibodies4 are expensive, suggesting that their wide use in topical chemoprophylaxis is unlikely. This emphasizes the importance of developing other methods for preventing HIV transmission. The target cells for sexual and mucosal HIV transmission include T lymphocytes, monocytes/macrophages and dendritic cells5. Therefore, compounds blocking HIV–CD4 binding are expected to inhibit virus transmission. In exploring the possibility that chemical modification of food proteins might lead to compounds with anti–HIV–1 activity, we found that bovine (β–lactoglobulin (β–LG) modified by 3–hydroxyphthalic anhydride (3HP–β–LC) (1) blocked at nanomolar concentrations the binding to CD4 of human (HIV) and simian (SIV) immunodeficiency virus surface glycoproteins and monoclonal antibodies specific for the HIV binding site on CD4 and (2) inhibited infection by HIV–1, including primary virus isolates, by HIV–2 and by SIV. The inexpensive and widely available source (whey) for production of 3HP–β–LG suggests its potential application (nonparenteral) for diminishing the frequency of HIV transmission.

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References

  1. Mann, J.M., Tarantola, D.J.M. & Netter, T.W. AIDS in the World (Harvard University Press, Cambridge, 1992).

    Google Scholar 

  2. Bird, K.D. The use of spermicide containing nonoxynol-9 in the prevention of HIV infection. AIDS 5, 791–796 (1991).

    Article  CAS  Google Scholar 

  3. Steele, F. AIDS drugs lurch towards market. Nature Med. 1, 285–286 (1995).

    Article  CAS  Google Scholar 

  4. Forthal, D.N., Landucci, G., Gorny, M.K., Zolla-Pazner, S. & Robinson, W.E., Jr., Functional activities of 20 human immunodeficiency virus type 1 (HIV-1)-specific human monoclonal antibodies. AIDS Res. Hum. Retrovir. 11, 1095–1099 (1995).

    Article  CAS  Google Scholar 

  5. Miller, C.J., McGhee, J.R. & Gardner, M.B. Biology of disease: Mucosal immunity, HIV transmission, and AIDS. Lab. Invest. 68, 129–145 (1992).

    Google Scholar 

  6. Sattentau, Q.J. et al. The human and simian immunodeficiency viruses HIV-1, HIV-2 and SIV interact with similar epitopes on their cellular receptor, the CD4 molecule. AIDS 2, 101–105 (1988).

    Article  CAS  Google Scholar 

  7. Healey, D. et al. Novel anti-CD4 monoclonal antibodies separate human immunodeficiency virus infection and fusion of CD4+ cells from virus binding. J. Exp. Med. 172, 1233–1242 (1990).

    Article  CAS  Google Scholar 

  8. Sattentau, Q.J. et al. Structural analysis of the human immunodeficiency virus-binding domain of CD4: Epitope mapping with site-directed mutants and anti-idiotypes. J. Exp. Med. 170, 1319–1334 (1989).

    Article  CAS  Google Scholar 

  9. Muller, R. Determination of affinity and specificity of anti-hapten antibodies by competitive radioimmunoassay. in Methods in Enzymology. Immunochemical Techniques. Part E. Monoclonal Antibodies and General Immunoassay Methods (eds Langone, J.J. & Van Vunakis, H.) 589–601 (Academic Press, 1983).

    Chapter  Google Scholar 

  10. Stoddard, B.L. & Koshland, D.E., Jr., Prediction of the structure of a receptor-protein complex using a binary docking method. Nature 358, 774–776 (1992).

    Article  CAS  Google Scholar 

  11. Garrett, T.P.J., Wang, J., Yan, Y., Liu, J. & Harrison, S.C. Refinement and analysis of the structure of the first two domains of human CD4. J. Mol. Biol. 234, 763–778 (1993).

    Article  CAS  Google Scholar 

  12. Sato, H., Orenstein, J., Dimitrov, D. & Martin, M. Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles. Virology 186, 712–724 (1992).

    Article  CAS  Google Scholar 

  13. Kimpton, J. & Emerman, M. Detection of replication-competent and pseudo-typed human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated β-galactosidase gene. J. Viral. 66, 2232–2239 (1992).

    CAS  Google Scholar 

  14. Allaway, G.P. et al. Expression and characterization of CD4-IgG2, a novel het-erotetramer that neutralizes primary HIV type 1 isolates. AIDS Res. Hum. Retroviruses 11, 533–539 (1995).

    Article  CAS  Google Scholar 

  15. Daar, E.S., Li, X.L., Moudgil, T. & Ho, D.D. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc. Natl. Acad. Sci. USA 87, 6574–6578 (1990).

    Article  CAS  Google Scholar 

  16. Morr, C.V. & Ha, E.Y.W. Whey protein concentrates and isolates: processing and functional properties. Crit. Rev. Food Sci. Nutr. 33, 431–476 (1993).

    Article  CAS  Google Scholar 

  17. Gartner, S. & Popovic, M. Virus isolation and production. in Techniques in HIV Research (eds Aldovini, A. & Walker, B.D.) 53–70 (Stockton, New York, 1990).

    Chapter  Google Scholar 

  18. Jiang, S., Lin, K., Strick, N. & Neurath, A.R. HIV-1 inhibition by a peptide. Nature 365, 113 (1993).

    Article  CAS  Google Scholar 

  19. Neurath, A.R., Strick, N., Haberfleld, P. & Jiang, S. 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. Chemother. 3, 55–63 (1992).

    Article  CAS  Google Scholar 

  20. Neurath, A.R., Strick, N. & Sproul, P. Search for hepatitis B virus cell receptors reveals binding sites for interleukin 6 on the virus envelope protein. J. Exp. Med. 175, 461–469 (1992).

    Article  CAS  Google Scholar 

  21. Kraulis, P.J. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J. Appl. Cryst. 24, 946–950 (1991).

    Article  Google Scholar 

  22. Monaco, H.L. et al. Crystal structure of the trigonal form of bovine beta-lac-toglobulin and of its complex with retinol at 2.5 Å resolution. J. Mol. Biol. 197, 695–706 (1987).

    Article  CAS  Google Scholar 

  23. Goodsell, D.S. & Olson, A.J. Automated docking of substrates to proteins by simulated annealing. Prot. Struct. Fund. Genet. 8, 195–202 (1990).

    Article  CAS  Google Scholar 

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Neurath, A., Jiang, S., Strick, N. et al. Bovine β–lactoglobulin modified by 3–hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV. Nat Med 2, 230–234 (1996). https://doi.org/10.1038/nm0296-230

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