Unique V3 Loop Sequence Derived from the R2 Strain of HIV-Type 1 Elicits Broad Neutralizing Antibodies

Young, Kelly R.; Teal, Benjamin E.; Brooks, Yvonne; Green, Thomas D.; Bower, Joseph F.; Ross, Ted M.

doi:10.1089/aid.2004.20.1259

Cited by 7 publications

(8 citation statements)

References 67 publications

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“…Consistent with previous studies from our laboratory 11,12,17,20,[30][31][32] , mice vaccinated with gp120-mC3d 3 -DNA elicited significantly higher titers of anti-Env-specific antibody compared to mice vaccinated with gp120-DNA (p > 0.05) (Figure 4). C3d enhanced anti-Env-specific antibodies, regardless of the route of vaccination.…”

Section: Anti-env Antibody Responsessupporting

confidence: 91%

“…The HIV-1 Env gp120 was conjugated to multimers of P28 and directly compared to elicitation of immune responses by Env gp120 conjugated to multimers of the full C3d protein. DNA vaccines expressing Env gp120 are poorly immunogenic when expressed from DNA, eliciting low anti-Env immunity ( Figures 3 and 4, as well as 11,12,17,20,[30][31][32] ); however, the HIV-1 envelope is highly immunogenic when presented to the immune system as a purified protein 30,[35][36][37][38][39][40][41][42][43][44][45][46][47][48] . Fusion of multimers of the whole C3d or the P28 peptide to Env gp120 enhanced the level of immunogenicity, regardless of the route of inoculation of DNA.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids were constructed to express a soluble form of HIV-1 envelope gp120 (Env gp120 ) using a wild-type gene sequence from HIV-1 isolate ADA 11,12,20,[30][31][32] . The first 32 amino acids were deleted from the N terminus of gp120 and replaced with a leader sequence from the trypsin plasminogen activator (tpA).…”

Section: Plasmid Dnamentioning

confidence: 99%

“…Therefore, in this study we directly compared the elicitation of humoral and cellular immune responses by a C3d conjugated antigen to a P28 peptide conjugated to a poorly immunogenic antigen expressed from a DNA vaccine or as purified proteins. Multimers of each adjuvant were conjugated to the well characterized HIV-1 Env gp120 11,12,20,[30][31][32] . When expressed from a DNA plasmid in vivo, Env gp120 elicits little or no anti-Env immunity.…”

Section: Introductionmentioning

confidence: 99%

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A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

Bower

Ross

Advances in Experimental Medicine and Biology

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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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Section: Anti-env Antibody Responsessupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Plasmid Dnamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

Bower

Ross

Advances in Experimental Medicine and Biology

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“…We focused on and tested a collection of outer domain-specific CD4i MAbs against envelopes from several HIV-1 strains: gp120 from clade B strains BaL, CDC451, YU2, JR-FL, and R2 in addition to trimeric BG505 SOSIP.664 gp140 and the BG505 gp120 monomer (clade A). The BG505 SOSIP.664 trimer was used to ascertain the effects of trimerization on CD4i MAb binding, while the R2 strain can infect CD4-negative cells (67), constitutively exposes several CD4i epitopes (68), and therefore could theoretically bind CD4i MAbs in the absence of CD4.…”

Section: Resultsmentioning

confidence: 99%

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

Kaplan

Roitburd-Berman

Lewis

et al. 2016

J Virol

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The HIV envelope binds cellular CD4 and undergoes a range of conformational changes that lead to membrane fusion and delivery of the viral nucleocapsid into the cellular cytoplasm. This binding to CD4 reveals cryptic and highly conserved epitopes, the molecular nature of which is still not fully understood. The atomic structures of CD4 complexed with gp120 core molecules (a form of gp120 in which the V1, V2, and V3 loops and N and C termini have been truncated) have indicated that a hallmark feature of the CD4-bound conformation is the bridging sheet minidomain. Variations in the orientation of the bridging sheet hairpins have been revealed when CD4-liganded gp120 was compared to CD4-unliganded trimeric envelope structures. Hence, there appears to be a number of conformational transitions possible in HIV-1 monomeric gp120 that are affected by CD4 binding. The spectrum of CD4-bound conformations has been interrogated in this study by using a well-characterized panel of conditional, CD4-induced (CD4i) monoclonal antibodies (MAbs) that bind HIV-1 gp120 and its mutations under various conditions. Two distinct CD4i epitopes of the outer domain were studied: the first comprises the bridging sheet, while the second contains elements of the V2 loop. Furthermore, we show that the unliganded extended monomeric core of gp120 (core e ) assumes an intermediate CD4i conformation in solution that further undergoes detectable rearrangements upon association with CD4. These discoveries impact both accepted paradigms concerning gp120 structure and the field of HIV immunogen design. IMPORTANCE Elucidation of the conformational transitions that the HIV-1 envelope protein undergoes during the course of entry into CD4؉ cells is fundamental to our understanding of HIV biology. The binding of CD4 triggers a range of gp120 structural rearrangements that could present targets for future drug design and development of preventive vaccines. Here we have systematically interrogated and scrutinized these conformational transitions using a panel of antibody probes that share a specific preference for the CD4i conformations. These have been employed to study a collection of gp120 mutations and truncations. Through these analyses, we propose 4 distinct sequential steps in CD4i transitions of gp120 conformations, each defined by antibody specificities and structural requirements of the HIV envelope monomer. As a result, we not only provide new insights into this dynamic process but also define probes to further investigate HIV infection. V iral tropism is mediated by the specific binding of the viral spike protein to its corresponding cell surface receptor. Evolution has driven human immunodeficiency virus (HIV) to elaborate on this canonical paradigm, introducing a series of orchestrated sequential events involving two receptors: CD4 as a primary receptor (1-3) and a chemokine receptor (CXCR4 or CCR5) as a subsequent coreceptor (4-10). However, many critical details of the molecular mechanisms by which CD4 triggers a number of conformati...

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Elicitation of neutralizing antibodies by intranasal administration of recombinant vesicular stomatitis virus expressing human immunodeficiency virus type 1 gp120

Jiang

Liu

Yin

et al. 2006

Biochemical and Biophysical Research Communications

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Recombinant viral vectors are useful tools for AIDS vaccine development. However, expression of HIV-1 envelope genes using viral vectors has not been successful in the induction of potent neutralizing antibodies in vivo. We took advantage of the strong immunogenicity of vesicular stomatitis virus (VSV)-based vector and expressed HIV-1 HXB2 gp120 gene in the recombinant VSV. Our results showed that HIV-1 gp120 protein expressed by the recombinant VSV retained the native conformation of the protein to some degree and was recognized by two well-characterized broad anti-HIV-1 neutralizing monoclonal antibodies b12, 2G12. We further showed that only one time intranasal immunization with the recombinant VSV led to production of anti-HIV-1 anti-sera in mice. In addition, we found that the anti-sera had the ability to neutralize not only HXB2 envelope-pseudotyped HIV-1 viruses but also HIV-1 pseudotyped viruses with JRFL envelopes. These results suggest that HIV-1 gp120 expressed by the recombinant VSV, in combination with the route of intranasal administration, is an effective strategy to evaluate the immunogenicity of HIV-1 envelope protein and its variants in mice.

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Unique V3 Loop Sequence Derived from the R2 Strain of HIV-Type 1 Elicits Broad Neutralizing Antibodies

Cited by 7 publications

References 67 publications

A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

Range of CD4-Bound Conformations of HIV-1 gp120, as Defined Using Conditional CD4-Induced Antibodies

Elicitation of neutralizing antibodies by intranasal administration of recombinant vesicular stomatitis virus expressing human immunodeficiency virus type 1 gp120

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