Abstract
The Bridging Sheet domain of HIV-1 gp120 is highly conserved among the HIV-1 strains and allows HIV-1 binding to host cells via the HIV-1 coreceptors. Further, the bridging sheet domain is a major target to neutralize HIV-1 infection. We rationally designed four linear peptide epitopes that mimic the three-dimensional structure of bridging sheet by using molecular modeling. Chemically synthesized peptides BS3 and BS4 showed a fair degree of antigenicity when tested in ELISA with IgG purified from HIV+ broadly neutralizing sera while the production of synthetic peptides BS1 and BS2 failed due to their high degree of hydrophobicity. To overcome this limitation, we linked all four BS peptides to the COOH-terminus of GST protein to test both their antigenicity and immunogenicity. Only the BS1 peptide showed good antigenicity; however, no envelope specific antibodies were elicited upon mice immunization. Therefore we performed further analyses by linking BS1 peptide to the NH2-terminus of the E2 scaffold from the Geobacillus Stearothermophylus PDH complex. The E2-BS1 fusion peptide showed good antigenic results, however only one immunized rabbit elicited good antibody titers towards both the monomeric and oligomeric viral envelope glycoprotein (Env). In addition, moderate neutralizing antibodies response was elicited against two HIV-1 clade B and one clade C primary isolates. These preliminary data validate the peptide mimotope approach as a promising tool to obtain an effective HIV-1 vaccine.
Highlights
Neutralizing antibodies (Nabs) play a key role in controlling viral infections and contribute to the protective effect of many successful vaccines [1]
We focused on the bridging sheet domain of gp120 env protein because it contains amino acidic sequences essential for the CD4 and the coreceptor binding, together with
The choice of E2 multimeric subunit allowed the complex structural refolding as a 20-trimer which is a suitable carrier for the mimotope BS1 presentation to the immune system, since it could mimic the trimeric structure of envelope glycoprotein (Env) spike
Summary
Neutralizing antibodies (Nabs) play a key role in controlling viral infections and contribute to the protective effect of many successful vaccines [1]. Neutralizing antibodies bind viral particles preventing viral infection of host target cells and blocking subsequent replication cycles. Infection relies on the identification of immunogens able to elicit broadly neutralizing responses [3]. Most of type-specific and broadly cross-reactive neutralizing antibodies elicited during HIV-1 natural infection are mainly directed against HIV-1 Env glycoproteins gp120 and gp, that play a major role for viral attachment and entry into target cells [4]. The initial antibody response to HIV-1 is primarily directed against non-neutralizing epitopes on envelope glycoproteins gp120 and gp (Env) [5,6]
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