Chemokine Binding Protein vCCI Attenuates Vaccinia Virus Without Affecting the Cellular Response Elicited by Immunization with a Recombinant Vaccinia Vector Carrying the HPV16 E7 Gene

Abstract

Viral CC chemokine inhibitor (vCCI) of the clone P13 vaccinia virus (VACV) strain PRAHA lacks eight amino acids in the signal peptide sequence. To study the influence of vCCI on virus biology, a virus with the vCCI gene coding for a prolonged signal sequence was prepared. We found that secreted vCCI attenuated the virus in vivo, and that it correlated with decreased levels of RANTES, eotaxin, TARC, and MDC in the blood in comparison with the parental virus. We determined the influence of vCCI on the CTL response against VACV E3((140-148)) (VGPSNSPTF) and HPV16 E7((49-57)) (RAHYNIVTF) H-2D(b)-restricted epitopes. The examination of the specific CTL response elicited by immunization with the recombinant VACV-expressing tumor-associated HPV16 E7 antigen by IFN-γ ELISPOT showed that the immunogenicity of the recombinant VACV-producing secretory vCCI was similar to that of the parent virus or deletion mutant in the C23L/B29R locus. Immunization with the secretory vCCI-producing recombinant virus has a lower therapeutic anti-tumor effect against TC-1 tumors. Viral CCI downregulated the E7-specific response induced by gene gun immunization with the DNA vaccines pBSC-SigE7 LAMP and pBSC-vCCI. We also observed that the immune response against vCCI elicited by the DNA vaccine did not affect the multiplication of VACV in vivo.

Structural Insights into the Interaction between a Potent Anti-inflammatory Protein, Viral CC Chemokine Inhibitor (vCCI), and the Human CC Chemokine, Eotaxin-1

“…A comprehensive analysis of the binding profile of vCCI with an extensive panel of more than 80 chemokines revealed that vCCI binds to 26 CC chemokines with high affinity, including 14 human chemokines, such as eotaxin, MCP-1, MIP-1␣, MIP-1␤, and RANTES (24). Although vCCI possesses no close molecular similarity to known mammalian or other eukaryotic proteins (13,63), its broad spectrum, high affinity CC chemokine binding ability suggests that it might provide further clues as to how to develop specific therapeutic agents to abrogate chemokine-mediated disease conditions.…”

Antitumor activity and immunogenicity of recombinant vaccinia virus expressing HPV 16 E7 protein SigE7LAMP is enhanced by high-level coexpression of IGFBP-3

“…The response of interferon-g-producing cells was determined by enzyme-linked immunosorbent spot (ELISPOT) in the ex vivo setting, as described previously. 50 Lymphocytes were stimulated with H-2Db-restricted HPV16 E7(49-57) (RAHYNIVTF) or VACV E3(140-148) (VGPSNSPTF) peptide for 20 h. 56…”

“…All three recombinant viruses induced cytotoxic T lymphocyte responses against the HPV16 E7 nonapeptide. [49][50][51][52][53][54][55][56][57] Coexpression of IGFBP-3 enhanced the E7-specific response only subtly. The enhancement of the T-cell response by IGFBP-3 coexpression was more apparent against the VACV E3-derived peptide in mice receiving P13-SigE7Lamp-H5-IGFBP-3 and P13-SigE7Lamp-E/L-IGFBP-3.…”

Immune Responses in Oral Papillomavirus Clearance in the MmuPV1 Mouse Model

“…These immune cells play a critical role in the link between innate and adaptive immunity and activating adaptive immune responses to counteract local papillomavirus infections [20,[26][27][28][29]. Chemokines and their receptors are vital factors for the trafficking of immune cells to these locally impacted tissues [25,[30][31][32]. Chemokines expressed by virally infected cells can facilitate the recruitment of these immune cells [32,33].…”

“…Chemokines expressed by virally infected cells can facilitate the recruitment of these immune cells [32,33]. Two papillomavirus oncoproteins, E6 and E7, play a role in repressing chemokine expression in infected cells and therefore impede the migratory capacity of Langerhans cells during the development of advanced HPV diseases such as cervical cancer [25,31,34]. Dendritic cells (DCs), monocytes, and macrophages are members of the mononuclear phagocyte system that display multiple functions during immune responses.…”