Preclinical studies on immunogenicity of the HIV‐1 p17‐based synthetic peptide AT20‐KLH

Abstract

Several studies have suggested that HIV-1 p17 matrix protein may play an important role in AIDS pathogenesis, since anti-p17 antibodies represent a serological marker of disease progression during HIV-1 infection both in adults and children. Moreover, it has been recently reported that the viral protein is capable of significantly increasing the proliferation of preactivated T lymphocytes and the release of proinflammatory cytokines. Recombinant HIV-1 p17 also has induced an increased rate of HIV-1 replication in vitro. All p17 biological activities are exerted after its binding to a specific cellular receptor expressed on activated T lymphocytes. The functional p17 epitope involved in receptor binding was found to be located at the NH(2)-terminal region of the viral protein. Immunization of C57BL/6 mice with a 20 amino acid synthetic peptide representative of the HIV-1 p17 functional region (AT20) coupled to the carrier protein keyhole limpet hemocyanin (KLH) and given in Freund's incomplete adjuvant, resulted in the development of p17-neutralizing antibodies capable of blocking p17/p17 receptor interaction, and consequently, all biological activities of the viral protein. Moreover, it was possible to skew the humoral response induced by priming mice with AT20-KLH toward cell-mediated immune responses, boosting animals with p17. Our findings may provide a new strategy to develop a synthetic AIDS vaccine based on a potentially effective and safe subunit vaccine against the HIV-1 cytokine-like matrix protein p17. Preclinical immunogenicity data for AT20-KLH provide the basis for evaluation of the peptide-based vaccine, alone and in combination with p17 or p17 DNA vaccines, in Phase I clinical trials.

Molecular Interaction Studies of HIV-1 Matrix Protein p17 and Heparin

“…Interestingly, the extracellular N-terminal domain of CXCR1 is highly negatively charged (53), and the N-terminal basic motif 25 GKKKYKLKHI 34 of p17 partially overlaps with the p17 receptor binding domain 9 SGGELDRWEKIRLRPGG-KKK 28 (54). These observations prompted us to investigate whether neutralization of the basic amino acids of the N-terminal basic motif of p17 affected the interaction of the protein to the chemokine receptor.…”

HIV-1 Matrix Protein p17 Promotes Lymphangiogenesis and Activates the Endothelin-1/Endothelin B Receptor Axis

“…45 This may be achieved by using p17-specific drugs 46 or by specific vaccines aimed to generate a neutralizing p17 antibody response. 47 The knowledge that p17 triggers common pathways of lymphangiogenesis and angiogenesis, which represent important routes of metastasis, may offer new opportunities to identify novel treatment strategies in preventing and combating ARLs.…”

HIV-1 matrix protein p17 binds to the IL-8 receptor CXCR1 and shows IL-8–like chemokine activity on monocytes through Rho/ROCK activation

“…32 Site I binding results in conformational changes that are essential for the receptor exoloops and transmembrane residues (site II) 33 to interact with the IL-8 N-terminal Glu-Leu-Arg (ELR) residues and trigger downstream signaling events for function. 32 The p17 domain responsible for receptor interaction resides in a partially unfolded ␣-helix forming a loop within the N-terminus of viral protein 34 (Figure 7). Moreover, an ELR motif is included between aa 74-76, whereas 2 other ELR-like motifs, The association rate (Kon) and dissociation rate (Koff) are reported and the dissociation constant (Kd) was derived from the Koff/Kon ratio.…”