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185 Interaction between a domain in the fusion peptide proximal region (FPPR) of gp41 and the epitope domain in the membrane proximal external region (MPER) increases binding of 2F5 to its epitope

Fiebig, Uwe; Eschricht, Magdalena; Schmolke, Mirco; Kurth, Reinhard; Denner, Joachim

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JAIDS Journal of Acquired Immune Deficiency Syndromes: June 2009 - Volume 51 - Issue -
doi: 10.1097/01.qai.0000351140.40327.b2
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Neutralizing antibodies such as 2F5 and 4E10 have been isolated from HIV-1 infected patients. They recognize epitopes in the MPER of gp41 and neutralize a broad range of HIV strains. Previously we reported induction of neutralising antibodies against the porcine endogenous retrovirus (PERV), the feline leukaemia virus (FeLV) and the Koala retrovirus (KoRV) by immunization with the ectodomain of their transmembrane envelope (TM) proteins p15E. Antisera obtained in rats, goats and cats recognized two epitopes: One, designated E1, was located in the FPPR and the other was located in the MPER of p15E (E2). E2 corresponded to the 2F5/4E10 epitope in gp41. Despite the evolutionary distance between HIV on one hand and PERV, FeLV and KoRV on the other, limited sequence homology exists (F/YEGWFN in the case of gammaretroviruses and NWFNIT, the 4E10 epitope, in the case of HIV-1, identical amino acids underlined). Immunising cats with p15E of FeLV resulted in protection from FeLV infection in vivo.

Using ELISA, epitope mapping and surface plasmon resonance analysis we also identified an E1 domain in the FPPR of gp41 of HIV and showed that the interaction of peptides containing E1 significantly increased the binding of 2F5 to peptides containing the E2 (2F5/4E10 epitope) domain. In addition, neutralisation of HIV-1 by 2F5 was inhibited more effectively with both gp41-derived peptides E1 and E2 than with peptide E2 alone.

Since E1 peptides increased the interaction of 2F5 with peptides containing its E2/ELDKWA epitope, it is most likely that both domains are required to induce neutralizing antibodies (WO 2005/021574, WO 2007/107597). This strategy may be used to generate a vaccine inducing broadly neutralising antibodies to prevent or curtail HIV infection.<!?A3B2 tpb=6pt?>

© 2009 Lippincott Williams & Wilkins, Inc.