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12 A Novel Virus-Receptor Immunization Strategy toward SIV or HIV
T. Lehner*1, W. M. J. M. Bogers2, H. Oostermeijer2, J. L. Heeney2, J. Ma1, L. A. Bergmeier1, M. Singh3, Y. Wang1, K. Babaahmady1, G. Balarajah1, and C. G. Kelly1
1Guy’s, King’s & St Thomas’ Hosp. Med. Sch., London, UK; 2Biomedical Res. Ctr., Rijswijk, The Netherlands; and 3Lionex Diagnostics & Therapeutics, Braunschweig, Germany
Background: The cell-surface CCR5 receptor has been subverted by R5 HIV-1 and SIV to serve as a coreceptor to the CD4 glycoprotein that enables viral entry into the cell. The objectives of this study were to use a dual virus-receptor immunization strategy in preventing SIV or HIV infection by blocking and down-modulating CCR5, in addition to inducing specific immune responses to the viral antigens.
Methods: We used the 70-kD heat shock protein (HSP70) for its dual function: generating CC chemokines that have adjuvant activity and block CCR5 receptors. To enhance the inhibiting effect of the CC chemokines, we linked the N-terminal 1st and 2nd loop of CCR5 to HSP70 to induce antibodies to CCR5. For specific anti-viral immunity, SIV gp120 and p27 were linked to HSP70. An HIV gp120 fragment was expressed by transgenic plant biotechnology in tobacco plants. The vaccine was administered by the I.M. or vaginal route of immunization (X3).
Results: Systemic or mucosal immunization with the HSP70-linked antigens elicited SIV- (or HIV-) and CCR5-specific IgG and IgA antibodies and T-cell proliferation, but mucosal antibodies only after vaginal immunization. I.V. challenge with SIV 8980 of the I.M.-immunized macaques showed that 2 of 4 macaques immunized with the CCR5 peptides and SIV antigens linked to HSP70 showed either total protection or a decrease in the plasma viral load, unlike the 9 unimmunized or SIVgp120- and p27-immunized macaques. Vaginal challenge with SHIV 89.6P after vaginal immunization with HSP70 linked to HIVgp120, SIVp27, and the CCR5 peptides elicited a decrease in the plasma viral load, as compared with the unimmunized controls.
Conclusions: A novel virus-receptor immunization strategy elicited specific IgG and IgA antibodies to CCR5, SIV or HIV, CD4+ T-cell proliferation, CD8+ T-cell suppressor factors, RANTES, MIP-1?? and MIP-1?. Transgenic plant HIV gp120 was immunogenic when applied by the vaginal mucosal route. Decreased viral load or no detectable virus was found in a proportion of macaques following systemic or mucosal immunization.
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