TY - JOUR
T1 - Immunogenicity of a novel engineered HIV-1 clade C synthetic consensus-based envelope DNA vaccine
AU - Yan, Jian
AU - Corbitt, Natasha
AU - Pankhong, Panyupa
AU - Shin, Thomas
AU - Khan, Amir
AU - Sardesai, Niranjan Y.
AU - Weiner, David B.
N1 - Funding Information:
This work was supported in part by NIH grants awarded to Dr. David B. Weiner. The DBW laboratory notes the following relationships are associated with this work and should be acknowledged DBW has received consulting fees, stock ownership, or has served on Advisory Boards or Review Board Service, or has received speaking support from the following companies: Pfizer, Inovio, BMS, VGXI, Virxsys, Ichor, Merck, Althea, Aldevron, Novartis, and possibly others.
PY - 2011/9/22
Y1 - 2011/9/22
N2 - DNA vaccines require significant engineering in order to generate strong CTL responses in both non-human primates and humans. In this study, we designed a clade C env gene (EY3E1-C) to decrease the genetic distances of virus isolates within clade C and focus the induced T cell responses to conserved clade C epitopes. After generating a consensus sequence by analyzing full-length clade C env early transmitter sequences, several modifications were performed to increase the expression of the EY3E1-C, including codon/RNA optimization, addition of Kozak sequence and addition of an IgE leader sequence. We also shortened the V1 and V2 loops to approximate early transmitter isolate sequences and the cytoplasmic tail was truncated to prevent envelope recycling. When studied as a DNA vaccine in Balb/c mice, compared to a primary codon-optimized clade C envelope DNA vaccine (p96ZM651gp140-CD5), this novel construct is up to three times more potent in driving CTL responses. Importantly this construct not only induces stronger cross-reactive cellular responses within clade C, it also induces stronger immune responses against clade B and group M envelope peptide pools than p96ZM651gp140-CD5. Epitope mapping demonstrated that EY3E1-C was able to induce clade C envelope-specific immune responses against 15 peptide pools, clade B envelope-specific immune responses against 19 peptide pools and group M envelope-specific immune responses against 16 peptide pools out of 29, respectively, indicating that a significant increase in the breadth of induced immune responses. The analysis of antibody responses suggested that vaccination of pEY3E1-C could induce a clade C envelope-specific antibody response. The cellular immune responses of pEY3E1-C could be further enhanced when the DNA was delivered by using electroporation (EP). Thus, the synthetic engineered consensus EY3E1-C gene is capable of eliciting stronger and broader CTL responses than primary clade C envelopes. This finding suggests that such synthetic immunogens could be important for examination of their potential as part of an efficient HIV DNA vaccine.
AB - DNA vaccines require significant engineering in order to generate strong CTL responses in both non-human primates and humans. In this study, we designed a clade C env gene (EY3E1-C) to decrease the genetic distances of virus isolates within clade C and focus the induced T cell responses to conserved clade C epitopes. After generating a consensus sequence by analyzing full-length clade C env early transmitter sequences, several modifications were performed to increase the expression of the EY3E1-C, including codon/RNA optimization, addition of Kozak sequence and addition of an IgE leader sequence. We also shortened the V1 and V2 loops to approximate early transmitter isolate sequences and the cytoplasmic tail was truncated to prevent envelope recycling. When studied as a DNA vaccine in Balb/c mice, compared to a primary codon-optimized clade C envelope DNA vaccine (p96ZM651gp140-CD5), this novel construct is up to three times more potent in driving CTL responses. Importantly this construct not only induces stronger cross-reactive cellular responses within clade C, it also induces stronger immune responses against clade B and group M envelope peptide pools than p96ZM651gp140-CD5. Epitope mapping demonstrated that EY3E1-C was able to induce clade C envelope-specific immune responses against 15 peptide pools, clade B envelope-specific immune responses against 19 peptide pools and group M envelope-specific immune responses against 16 peptide pools out of 29, respectively, indicating that a significant increase in the breadth of induced immune responses. The analysis of antibody responses suggested that vaccination of pEY3E1-C could induce a clade C envelope-specific antibody response. The cellular immune responses of pEY3E1-C could be further enhanced when the DNA was delivered by using electroporation (EP). Thus, the synthetic engineered consensus EY3E1-C gene is capable of eliciting stronger and broader CTL responses than primary clade C envelopes. This finding suggests that such synthetic immunogens could be important for examination of their potential as part of an efficient HIV DNA vaccine.
KW - Cellular immune responses
KW - Clade C
KW - Consensus
KW - Envelope
KW - HIV-1
UR - http://www.scopus.com/inward/record.url?scp=80052498736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052498736&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2011.05.076
DO - 10.1016/j.vaccine.2011.05.076
M3 - Article
C2 - 21651948
AN - SCOPUS:80052498736
SN - 0264-410X
VL - 29
SP - 7173
EP - 7181
JO - Vaccine
JF - Vaccine
IS - 41
ER -