Immune Complex Vaccine Strategies to Combat HIV-1 and Other Infectious Diseases

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding has been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Immune Complex Vaccine Strategies to Combat HIV-1 and Other Infectious Diseases

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

In silicodesign of glyco-D,L-peptide antiviral molecules

Backgroundmost licensed antiviral drugs are nucleoside analogs. A recent research focuses on blocking a virus from entering the cells in the viral cell adsorption/entry stage. In this entry mechanism the glycans present on the viral surface play a fundamental role. Homochiral L-peptides acting this fusion mechanism have shown some inhibition of viral infection. Peptides with regularly alternating enantiomeric sequence (L,D-peptides) can assume structures, which are not accessible to the corresponding homochiral molecules. Further, L,D-peptides are less sensitive to the enzymatic digestion.Aimin silicodesign a L,D-peptide with a high affinity for the viral surface glycans, and consequently able to interfere with its fusion mechanism.Methodsa 3α,6α-Mannopentaose (3-6MP) molecule was used to simulate a viral surface glycan. Molecular Dynamics (MD) simulations of 3-6MP and D,L-peptide in water are performed using the force field AMBER12-GLYCAM06i. The binding constant was evaluated from trajectories. The D,L-peptide molecule was modified over the sequence, the length, the terminals and finally glycosylated to attain a very high binding constant value for 3-6MP.In addition, the specific interaction between T lymphocyte CD4 glycoprotein and HIV envelope gp120 glycoprotein was studied through MD simulations between a D,L-peptide, bounded to a typical CD4 glycan, and a highly conserved HIV gp120 glycan.Resultsin the case of interaction with 3-6MP molecule, the very effective molecule obtained was H-D-Trp-L-Pro-D-Asn-L-Pro-D-Trp-L-Pro-D-Asn-L-Pro-OH where the Asn residues in position 3 and 7 are glycosylated with alpha-D-Mannopyranosyl-(1->3)-[alpha-D-mannopyranosyl-(1->6)]-alpha-D-mannopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-1-OH.In the case of interaction with HIV envelope, the very effective molecule obtained, able to antagonize the CD4 glycoprotein, was H-D-Trp-L-Pro-D-Asn-L-Pro-D-Trp-L-Pro-D-Asn-L-Pro-OH where the Asn residue in position 3 is glycosylated with alpha-D-galactopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->2)-alpha-D-Mannopyranosyl-(1->3)-[alpha-D-galactopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->2)-alpha-D-Mannopyranosyl-(1->6)]-beta-D-mannopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-(1->4)-N-acetyl-beta-D-glucopyranosyl-1-OHConclusionthese glycosylated D,L-peptide molecules are very promising representatives of a new class of antiviral agents.

Histidine 375 Modulates CD4 Binding in HIV-1 CRF01_AE Envelope Glycoproteins

ABSTRACT The envelope glycoproteins (Envs) from human immunodeficiency virus type 1 (HIV-1) mediate viral entry. The binding of the HIV-1 gp120 glycoprotein to CD4 triggers conformational changes in gp120 that allow high-affinity binding to its coreceptors. In contrast to all other Envs from the same phylogenetic group, M, which possess a serine (S) at position 375, those from CRF01_AE strains possess a histidine (H) at this location. This residue is part of the Phe43 cavity, where residue 43 of CD4 (a phenylalanine) engages with gp120. Here we evaluated the functional consequences of replacing this residue in two CRF01_AE Envs (CM244 and 92TH023) by a serine. We observed that reversion of amino acid 375 to a serine (H375S) resulted in a loss of functionality of both CRF01_AE Envs as measured by a dramatic loss in infectivity and ability to mediate cell-to-cell fusion. While no effects on processing or trimer stability of these variants were observed, decreased functionality could be linked to a major defect in CD4 binding induced by the replacement of H375 by a serine. Importantly, mutations of residues 61 (layer 1), 105 and 108 (layer 2), and 474 to 476 (layer 3) of the CRF01_AE gp120 inner domain layers to the consensus residues present in group M restored CD4 binding and wild-type levels of infectivity and cell-to-cell fusion. These results suggest a functional coevolution between the Phe43 cavity and the gp120 inner domain layers. Altogether, our observations describe the functional importance of amino acid 375H in CRF01_AE envelopes. IMPORTANCE A highly conserved serine located at position 375 in group M is replaced by a histidine in CRF01_AE Envs. Here we show that H375 is required for efficient CRF01_AE Env binding to CD4. Moreover, this work suggests that specific residues of the gp120 inner domain layers have coevolved with H375 in order to maintain its ability to mediate viral entry.

The antiviral lectin cyanovirin-N: probing multivalency and glycan recognition through experimental and computational approaches

CVN (cyanovirin-N), a small lectin isolated from cyanobacteria, exemplifies a novel class of anti-HIV agents that act by binding to the highly glycosylated envelope protein gp120 (glycoprotein 120), resulting in inhibition of the crucial viral entry step. In the present review, we summarize recent work in our laboratory and others towards determining the crucial role of multivalency in the antiviral activity, and we discuss features that contribute to the high specificity and affinity for the glycan ligand observed in CVN. An integrated approach that encompasses structural determination, mutagenesis analysis and computational work holds particular promise to clarify aspects of the interactions between CVN and glycans.