Limits...
Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs.

Feng H, Zhang H, Deng J, Wang L, He Y, Wang S, Seyedtabaei R, Wang Q, Liu L, Galipeau J, Compans RW, Wang BZ - Sci Rep (2015)

Bottom Line: Co-delivery of mucosal adjuvants has been shown to be essential to induce effective mucosal immunity by non-replicating vaccines.A novel cytokine, GIFT4, engineered by fusing GM-CSF and interleukin-4, was previously found to simulate B cell proliferation and effector function.Incorporation of GPI-anchored GIFT4 into VLPs as a molecular adjuvant represents a novel approach to increase their immunogenicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.

ABSTRACT
HIV vaccines should elicit immune responses at both the mucosal portals of entry to block transmission and systemic compartments to clear disseminated viruses. Co-delivery of mucosal adjuvants has been shown to be essential to induce effective mucosal immunity by non-replicating vaccines. A novel cytokine, GIFT4, engineered by fusing GM-CSF and interleukin-4, was previously found to simulate B cell proliferation and effector function. Herein a membrane-anchored form of GIFT4 was constructed by fusing a glycolipid (GPI)-anchoring sequence and incorporated into Env-enriched HIV virus-like particles (VLPs) as a molecular adjuvant. Guinea pigs were immunized with the resulting HIV VLPs through an intramuscular priming-intranasal boosting immunization route. The GIFT4-containing VLPs induced higher levels of systemic antibody responses with significantly increased binding avidity and improved neutralizing breadth and potency to a panel of selected strains, as well as higher levels of IgG and IgA at several mucosal sites. Thus, the novel GPI-GIFT4-containging VLPs have the potential to be developed into a prophylactic HIV vaccine. Incorporation of GPI-anchored GIFT4 into VLPs as a molecular adjuvant represents a novel approach to increase their immunogenicity.

No MeSH data available.


Related in: MedlinePlus

Avidity of immune serum IgG to selected pseudoviruses.Avidity assays were conducted with immune sera of bleed 3 (at week 10) from sVLP and cVLPs-immunized guinea pigs. a, avidity indexes of immune serum IgG to clade B pseudoviruses; b, avidity indexes of immune serum IgG to clade C pseudoviruses. Data are expressed as means ± standard deviations. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493578&req=5

f5: Avidity of immune serum IgG to selected pseudoviruses.Avidity assays were conducted with immune sera of bleed 3 (at week 10) from sVLP and cVLPs-immunized guinea pigs. a, avidity indexes of immune serum IgG to clade B pseudoviruses; b, avidity indexes of immune serum IgG to clade C pseudoviruses. Data are expressed as means ± standard deviations. *P < 0.05.

Mentions: Antibody avidity for the HIV antigen is low at the early stage of infection and increases as the infection progresses while antibody matures23. Neutralizing antibodies with increased avidity evolve during maturation. A significant increase in avidity has been reported after repeated antigen exposure24. Several recent studies have also shown correlations between the avidity of non-neutralizing antibodies and HIV protective efficacy252627. Therefore, antibody avidity analysis is an effective way to evaluate antibody quality for providing protection. To determine whether cVLPs induce antibody responses to Env with enhanced avidity, six Env-pseudotyped viruses from both clades B and C, were compared. Because Env is inserted into the pseudoviral envelope, as is the case in virions, Env in pseudoviruses and virions are functionally equivalent, binding to target cells and mediating virus-host cell membrane fusion. Pseudotyped virus-based neutralizing assays have been extensively used to evaluate an antibody capacity for blocking HIV infection. Thus antibody avidity to pseudovirus Env should reflect the antibody binding to HIV particles. The results shown in Fig. 5 demonstrated that serum antibodies in the cVLP group showed significantly increased avidity compared to the sera from the sVLP immunized group. As shown in Fig. 5, the cVLPs elicited antibodies with increased avidity with AIs around 40 for binding to 4 of the 6 clade B strains (Fig. 5a) as well as 4 of 6 clade C viruses (Fig. 5b), compared with sVLPs with AIs of no more than 20 (P < 0.05). Intermediate levels of avidity enhancement were found to strain 6535.3 in clade B and ZM214M.PL15 in clade C, and no change was observed with AC10.0.29 in clade B or ZM109F.PB4 (clade C) (P > 0.05). Interestingly, although cVLPs elicited increased avidity to sVLPs as observed above, avidity to Envs among these strains were not significantly different. Due to the much lower antibody levels in mucosal samples, avidity of both IgG and IgA in mucosal samples was not detectable, as is the case for serum IgA.


Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs.

Feng H, Zhang H, Deng J, Wang L, He Y, Wang S, Seyedtabaei R, Wang Q, Liu L, Galipeau J, Compans RW, Wang BZ - Sci Rep (2015)

Avidity of immune serum IgG to selected pseudoviruses.Avidity assays were conducted with immune sera of bleed 3 (at week 10) from sVLP and cVLPs-immunized guinea pigs. a, avidity indexes of immune serum IgG to clade B pseudoviruses; b, avidity indexes of immune serum IgG to clade C pseudoviruses. Data are expressed as means ± standard deviations. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493578&req=5

f5: Avidity of immune serum IgG to selected pseudoviruses.Avidity assays were conducted with immune sera of bleed 3 (at week 10) from sVLP and cVLPs-immunized guinea pigs. a, avidity indexes of immune serum IgG to clade B pseudoviruses; b, avidity indexes of immune serum IgG to clade C pseudoviruses. Data are expressed as means ± standard deviations. *P < 0.05.
Mentions: Antibody avidity for the HIV antigen is low at the early stage of infection and increases as the infection progresses while antibody matures23. Neutralizing antibodies with increased avidity evolve during maturation. A significant increase in avidity has been reported after repeated antigen exposure24. Several recent studies have also shown correlations between the avidity of non-neutralizing antibodies and HIV protective efficacy252627. Therefore, antibody avidity analysis is an effective way to evaluate antibody quality for providing protection. To determine whether cVLPs induce antibody responses to Env with enhanced avidity, six Env-pseudotyped viruses from both clades B and C, were compared. Because Env is inserted into the pseudoviral envelope, as is the case in virions, Env in pseudoviruses and virions are functionally equivalent, binding to target cells and mediating virus-host cell membrane fusion. Pseudotyped virus-based neutralizing assays have been extensively used to evaluate an antibody capacity for blocking HIV infection. Thus antibody avidity to pseudovirus Env should reflect the antibody binding to HIV particles. The results shown in Fig. 5 demonstrated that serum antibodies in the cVLP group showed significantly increased avidity compared to the sera from the sVLP immunized group. As shown in Fig. 5, the cVLPs elicited antibodies with increased avidity with AIs around 40 for binding to 4 of the 6 clade B strains (Fig. 5a) as well as 4 of 6 clade C viruses (Fig. 5b), compared with sVLPs with AIs of no more than 20 (P < 0.05). Intermediate levels of avidity enhancement were found to strain 6535.3 in clade B and ZM214M.PL15 in clade C, and no change was observed with AC10.0.29 in clade B or ZM109F.PB4 (clade C) (P > 0.05). Interestingly, although cVLPs elicited increased avidity to sVLPs as observed above, avidity to Envs among these strains were not significantly different. Due to the much lower antibody levels in mucosal samples, avidity of both IgG and IgA in mucosal samples was not detectable, as is the case for serum IgA.

Bottom Line: Co-delivery of mucosal adjuvants has been shown to be essential to induce effective mucosal immunity by non-replicating vaccines.A novel cytokine, GIFT4, engineered by fusing GM-CSF and interleukin-4, was previously found to simulate B cell proliferation and effector function.Incorporation of GPI-anchored GIFT4 into VLPs as a molecular adjuvant represents a novel approach to increase their immunogenicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.

ABSTRACT
HIV vaccines should elicit immune responses at both the mucosal portals of entry to block transmission and systemic compartments to clear disseminated viruses. Co-delivery of mucosal adjuvants has been shown to be essential to induce effective mucosal immunity by non-replicating vaccines. A novel cytokine, GIFT4, engineered by fusing GM-CSF and interleukin-4, was previously found to simulate B cell proliferation and effector function. Herein a membrane-anchored form of GIFT4 was constructed by fusing a glycolipid (GPI)-anchoring sequence and incorporated into Env-enriched HIV virus-like particles (VLPs) as a molecular adjuvant. Guinea pigs were immunized with the resulting HIV VLPs through an intramuscular priming-intranasal boosting immunization route. The GIFT4-containing VLPs induced higher levels of systemic antibody responses with significantly increased binding avidity and improved neutralizing breadth and potency to a panel of selected strains, as well as higher levels of IgG and IgA at several mucosal sites. Thus, the novel GPI-GIFT4-containging VLPs have the potential to be developed into a prophylactic HIV vaccine. Incorporation of GPI-anchored GIFT4 into VLPs as a molecular adjuvant represents a novel approach to increase their immunogenicity.

No MeSH data available.


Related in: MedlinePlus