Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

Bower, Joseph F.; Yang, Xinzhen; Sodroski, Joseph; Ross, Ted M.

doi:10.1128/jvi.78.9.4710-4719.2004

Cited by 78 publications

(90 citation statements)

References 71 publications

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“…Most studies that have compared the two forms using the same Env genotype have shown that gp140 trimers are superior to gp120 monomers at inducing neutralizing antibodies (19)(20)(21). However, the improvement in immunogenicity is not yet good enough to conclude that any forms of gp140 trimers, in their current iteration, are good enough to use in practical HIV-1 vaccines.…”

Section: Discussionmentioning

confidence: 95%

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Harris

Borgnia

Shi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

146

180

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The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env. viral entry | cryoelectron microscopy | HIV spike | HIV vaccine | AIDS vaccine

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Section: Discussionmentioning

confidence: 95%

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Harris

Borgnia

Shi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

146

180

View full text Add to dashboard Cite

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“…Recently, mice immunized with DNA plasmids expressing mC3d 3 fused to monomeric or trimeric forms of the HIV-1 envelope expressed from codon-optimized gene inserts elicited high titer anti-Env antibody [5,21]. Although, no differences were detected in the cell-mediated immune response in mice vaccinated with DNA expressing Env alone or conjugated to mC3d 3 from codon-optimized sequences [21].…”

Section: Introductionmentioning

confidence: 98%

“…Plasmids were constructed to express a soluble form of HIV-1 gp120 using wild type or synthetic genes optimized for expression in mammalian cells [2,18,37] from the HIV-1 isolates, YU-2, JR-FL, ADA, and R2 [5,16,21,32]. Each DNA vaccine was designated for the gene insert that the plasmid expressed.…”

Section: Methodsmentioning

confidence: 99%

“…Independently, each approach enhances antibody titer and cellular responses against Env compared to DNA plasmidsexpressing wild-type (wt) env gene inserts only. The fusion of C3d to an antigen results in enhanced immunogenicity to the fused antigen [5,16,17,19,21,24,31,32,35,36]. Rodents inoculated with DNA plasmids expressing HIV-1 Env fused to multiple copies of human or murine C3d (mC3d) had enhanced anti-Env specific IgG titers and accelerated affinity maturation of antibody [16].…”

Section: Introductionmentioning

confidence: 99%

“…Two recent approaches used to enhance the immunogenicity of Env expressed from a DNA vaccine are 1) the fusion of the molecular adjuvant, C3d, to a soluble form of Env [5,16,21,32,36] and 2) the use of codon-optimized (co) env gene inserts [5,11,18,21,37]. Independently, each approach enhances antibody titer and cellular responses against Env compared to DNA plasmidsexpressing wild-type (wt) env gene inserts only.…”

Section: Introductionmentioning

confidence: 99%

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C3d Enhances Immune Responses Using Low Doses of DNA Expressing the HIV-1 Envelope from Codon-Optimized Gene Sequences

Bower¹,

Sanders²,

Ross³

2005

CHR

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DNA vaccinations effectively induce both humoral and cellular immune responses to immunogens from diverse infectious agents. However, DNA vaccines expressing the HIV-1 envelope glycoprotein (Env) are poorly immunogenic when expressed from wild-type (wt) DNA sequences. Two recent approaches used to enhance the immunogenicity of Env expressed from a DNA vaccine are the fusion of the molecular adjuvant, C3d, to a soluble form of Env and the use of codon-optimized (co) env gene inserts. Independently, each approach enhances antibody titer and cellular responses against Env expressed from gene inserts. The goal of this study was to examine if both codon-optimization of env gene inserts and C3d conjugation to Env could function in a synergistic manner to enhance immunogenicity. Mice (BALB/c) were inoculated with decreasing doses (2.0 μg, 0.2 μg or 0.02 μg) of co DNA expressing Env alone or fused to three copies of murine C3d (mC3d 3 ) gene. Mice vaccinated with the highest dose (2.0 μg) of DNA had high anti-Env specific antibody titers regardless of the addition of mC3d 3 . At lower doses (0.2 μg and 0.02 μg) of DNA, mice vaccinated with EnvmC3d 3 had enhanced immune responses compared to mice vaccinated with DNA expressing Env only. In addition, mice vaccinated with Env-mC3d 3 at the highest doses of DNA had enhanced interleukin-4 secreting cells, while mice vaccinated with the lowest dose of DNA had enhanced interferon-gamma secreting cells. Therefore, both codon-optimization of env sequences and C3d conjugation to Env appear to enhance anti-Env antibodies in an independent and additive manner.

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A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

Bower

Ross

Advances in Experimental Medicine and Biology

Self Cite

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The degradation product of the third (C3) complement component, C3d, links innate and adaptive immunity, and the covalent attachment of C3d to an antigen enhances antigen-specific immune responses. C3d has been hypothesized to enhance immunity by direct interaction with complement receptor 2 (CR2/CD21) on immune cells. However, the domains on C3d important for CR2 binding have been controversial, with various studies reaching contradictory conclusions. In addition, the concept of B-cell activation via CR2 by C3d has been questioned, since mice lacking CR2 still elicit C3d-enhanced immunity following vaccination. Therefore, the goal of this study was to determine if a peptide representing one of the proposed CR2 binding domains of C3d could substitute for the entire protein and enhance antigen-specific immunity. Mice (BALB/c) were vaccinated with the HIV-1 gp120 envelope glycoprotein (Env(gp120)) alone or fused to multiple copies of the murine C3d or a twenty-eight amino-acid peptide (P28) containing a minimum CR2 binding domain. Each immunogen was expressed from DNA plasmid in vivo or injected as purified recombinant protein. The fusion of the P28 peptide to Env(gp120) enhanced both humoral and cell-mediated immune responses with similar efficiency as Env(gp120) conjugated to C3d. The fusion of C3d or P28 to Env(gp120) elicited higher-titer anti-Env specific antibody, enhanced avidity maturation of the elicited antibody, and elicited higher numbers of IFN-gamma and IL-4 secreting cells compared to Env(gp120) immunizations. This CR2-binding domain specific 28 amino acid peptide can substitute for the entire C3d molecule and enhance immunity. These results indicate that the adjuvant properties of C3d are associated with CR2 interaction.

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Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

Cited by 78 publications

References 71 publications

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

C3d Enhances Immune Responses Using Low Doses of DNA Expressing the HIV-1 Envelope from Codon-Optimized Gene Sequences

A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

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