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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

Neutralizing activity.Immune sera of the bleed 3 from sVLPs and cVLP-immunized animals were tested for neutralizing activity. The final dilution factor of immune sera was 40-fold. a, neutralization against clade B pseudoviruses. b, neutralization against clade C pseudoviruses. Data were expressed as means ± standard deviations. *P < 0.05.
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f6: Neutralizing activity.Immune sera of the bleed 3 from sVLPs and cVLP-immunized animals were tested for neutralizing activity. The final dilution factor of immune sera was 40-fold. a, neutralization against clade B pseudoviruses. b, neutralization against clade C pseudoviruses. Data were expressed as means ± standard deviations. *P < 0.05.

Mentions: Neutralizing antibodies can directly block viral infection by binding tightly to the functional Env, mediating entry inhibition, virus aggregation, complement-dependent inactivation, or triggering antibody-dependent cell-mediated cytotoxicity/virus inhibition (ADCC/ADCVI)282930, and thus are ideal targets to be elicited by a vaccine. Our results demonstrate that HIV cVLPs containing GPI-anchored GIFT4 induced higher titers of IgG compared to sVLPs. We further investigated the neutralization reactivity of these antibodies using a panel of HIV clade B and C Env-pseudoviruses, the same virus panel as was used to compare antibody binding avidity in Fig. 5. As shown in Fig. 6a, serum neutralizing reactivity elicited by the cVLP group against PVO.4, a tier 3 virus which shows strong resistance to neutralization31, and RHPA4259.7 (tier 2) were enhanced (approximately 30%–40% of the viruses were neutralized to lower than 20, P < 0.05) compared to the sVLP group. Of the 6 clade C viruses tested, immune sera from the cVLP group exhibited enhanced neutralization to Du156.12 (tier 2), ZM214M.PL15 (tier 2) and ZM109F.PB4 (intermediate) compared to the sVLP group (P < 0.05) (Fig. 6b). GIFT4-containing VLP and sVLP groups showed similar neutralization titers to the other viruses (P > 0.05). These results further indicate an adjuvant effect of the membrane-anchored GIFT4 in cVLPs in inducing antibody responses with enhanced neutralizing breadth and potency.


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)

Neutralizing activity.Immune sera of the bleed 3 from sVLPs and cVLP-immunized animals were tested for neutralizing activity. The final dilution factor of immune sera was 40-fold. a, neutralization against clade B pseudoviruses. b, neutralization against clade C pseudoviruses. Data were 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

f6: Neutralizing activity.Immune sera of the bleed 3 from sVLPs and cVLP-immunized animals were tested for neutralizing activity. The final dilution factor of immune sera was 40-fold. a, neutralization against clade B pseudoviruses. b, neutralization against clade C pseudoviruses. Data were expressed as means ± standard deviations. *P < 0.05.
Mentions: Neutralizing antibodies can directly block viral infection by binding tightly to the functional Env, mediating entry inhibition, virus aggregation, complement-dependent inactivation, or triggering antibody-dependent cell-mediated cytotoxicity/virus inhibition (ADCC/ADCVI)282930, and thus are ideal targets to be elicited by a vaccine. Our results demonstrate that HIV cVLPs containing GPI-anchored GIFT4 induced higher titers of IgG compared to sVLPs. We further investigated the neutralization reactivity of these antibodies using a panel of HIV clade B and C Env-pseudoviruses, the same virus panel as was used to compare antibody binding avidity in Fig. 5. As shown in Fig. 6a, serum neutralizing reactivity elicited by the cVLP group against PVO.4, a tier 3 virus which shows strong resistance to neutralization31, and RHPA4259.7 (tier 2) were enhanced (approximately 30%–40% of the viruses were neutralized to lower than 20, P < 0.05) compared to the sVLP group. Of the 6 clade C viruses tested, immune sera from the cVLP group exhibited enhanced neutralization to Du156.12 (tier 2), ZM214M.PL15 (tier 2) and ZM109F.PB4 (intermediate) compared to the sVLP group (P < 0.05) (Fig. 6b). GIFT4-containing VLP and sVLP groups showed similar neutralization titers to the other viruses (P > 0.05). These results further indicate an adjuvant effect of the membrane-anchored GIFT4 in cVLPs in inducing antibody responses with enhanced neutralizing breadth and potency.

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