Antibody VH domain sequence analysis by a bioinformatics approach based on electronic amino acid properties may help to predict paratop location.

Gene as the basic functional unit of DNA encodes information about the product such as protein. The majority of proteins realize function through protein-protein interactions involving short protein motifs. However, some proteins such as antibodies are established by the rearrangement of several (V-D-J) gene segments with the potential addition of nontemplated nucleotides that may change information encoded by the respective gene segment used.

A Model for Potential B-cell Precursors of Broadly Neutralizing HIV-1 Antibodies Selection and Antibody Affinity Maturation.

The goal of this report was to propose a model, wherein synergy between the B-cell antigen receptor (BCR) and toll-like receptor (TLR) signaling is involved in the selection of the B-cell precursors of HIV-1 broadly neutralizing antibodies (bnAbs) with long heavy chain complementarity determining regions 3, from immature/transitional B cells. The model predicts the involvement of Ab/HIV-1 complexes in a way that Ab from the complex binds both BCRs and HIV-1, while on internalization of HIV-1 TLR ligands such as CpG motifs interacts with TLR9. The result of BCR and TLR9 orchestrated signaling is a formation of somatically mutated memory B cells potential precursors of bnAbs.

Antibody Epitope Specificity for dsDNA Phosphate Backbone Is an Intrinsic Property of the Heavy Chain Variable Germline Gene Segment Used.

Analysis of protein sequences by the informational spectrum method (ISM) enables characterization of their specificity according to encoded information represented with defined frequency (F). Our previous data showed that F(0.367) is characteristic for variable heavy chain (VH) domains (a combination of variable (V), diversity (D) and joining (J) gene segments) of the anti-phosphocholine (PC) T15 antibodies and mostly dependent on the CDR2 region, a site for PC phosphate group binding.

Cooperation of intrathymic T15 idiotype-bearing B and complementary T cells in ontogeny of natural Treg cells involved in establishment of T15 clonal dominance.

The mechanisms for dominant T15 idiotype selection are not well understood, yet the significance of idiotypic regulation has been suggested. We proposed that to become dominant V regions of a given subset of B-1a cell must establish a functional idiotypic network with complementary T cells. Features required for the cells involved in immune network and steps preceding the establishment of clonal dominance are suggested.

Phosphocholine-binding antibody activities are hierarchically encoded in the sequence of the heavy-chain variable region: dominance of self-association activity in the T15 idiotype.

A methodology based on the representation of each amino acid of a protein sequence by the electron-ion interaction potential and subsequent analysis by signal processing was used to determine the characteristic or common frequency (in Hz) that reflects the biological activity shared among phosphocholine (PC)-binding antibodies. The common frequency for the variable portion of the heavy chain (VH) of the PC-specific antibodies is found to be at f = 0.37 Hz.

Naturally occurring V region connected antibodies inhibit anti-dsDNA antibody reactivity with dsDNA.

The production of autoantibodies against a vast array of self antigens, most notably double stranded (ds) DNA, characterized systemic lupus erythematosus (SLE). The purpose of this work is to study specific Ig fractions isolated from normal human serum (NHS) and their effect on the binding of anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies (Abs) to dsDNA. A fraction named immunoglobulin G (IgG)-reactive IgG was purified from total NHS IgG by absorption onto (CNBr)-activated Sepharose 4B linked to intact IgG molecules (IgG-Sepharose column).

Immunoglobulin G-reactive antibodies from sera of healthy individuals enriched in IgG2--therapeutic potential in HIV-1 infection.

Objective: To characterize the functional properties of natural autoantibodies capable of preventing in vitro infection by HIV-1, present in normal human serum (NHS), and denoted as IgG-reactive antibodies.

Methods: IgG-reactive antibodies were affinity purified both from normal human serum (NHS) and from a GammaBind G Sepharose Flowthrough (GBF) fraction of NHS by affinity chromatography on IgG coupled to CNBr-activated Sepharose (IgG-Sepharose).

Results: The GBF fraction was shown, by Capture ELISA relative to isotype-matched standards, to contain in addition to IgM and IgA isotypes, a low but constant level of IgG isotype.

Anti-IgG antibodies from sera of healthy individuals neutralize HIV-1 primary isolates.

Immunoglobulins (Ig) of pooled healthy human sera were purified by affinity chromatography based on their reactivity with human IgG. This Ig fraction represent connected, natural antibodies (NAbs) and here are denoted as anti-IgG antibodies. The data revealed that IgG, IgA and IgM isotypes are constituents of anti-IgG fraction.

Antibodies reactive with C-terminus of the second conserved region of HIV-1gp120 as possible prognostic marker and therapeutic agent for HIV disease.

It has been reported that antibodies reactive with peptide RSANFTDNAKTIIVQLNQSVEIN (peptide NTM) derived from the C-terminus of the second conserved domain of HIV-1 envelope glycoprotein gp120 could represent an important factor in control of the HIV disease. In order to check this notion we (i) tested reactivity with peptide NTM serum samples collected from 310 consecutive HIV-1 infected patients with a CD4(+) lymphocyte count ranging from 10 to 800/microL and (ii) performed the longitudinal study that included 107 sera samples collected from 29 HIV patients. Results of these studies demonstrated correlation between presence of anti-NTM antibodies in sera of HIV patients and disease progression measured by the CD4(+) cell count.

Application of VIP/NTM-reactive natural antibodies in therapy of HIV disease.

In sera of HIV-infected individuals natural antibodies recognizing nonimmunogenic C-terminal domain of the second conserved region of HIV-1 gp120 and the vasoactive intestinal peptide (VIP) were identified. It has been demonstrated that these antibodies are significantly more prevalent in asymptomatic carriers than in AIDS patients and that their titer strongly correlates with disease progression. These findings point out the VIP/C2-reactive natural antibodies as an important agent for immunotherapy of HIV disease.

HIV-1 gp120 and immune network.

It has been demonstrated that the immunodominant V3 loop of HIV-1 gp120 and its flanking regions bear sequence and structural homology to the framework and complementarity-determining regions of human immunoglobulins. It has been proposed that the Ig-like domain of gp120 might encode idiotypes and in this way permit HIV-1 entry into the immune regulatory network. This notion is strongly supported by results demonstrating that the anti-V3 loop and anti-Ig antibodies of healthy individuals share complementary structure and that V3 reactive antibodies are present in HIV-negative sera.

Molecular makeup of HIV-1 envelope protein.

A broad range of structural, functional, and immunological similarities between HIV-1 gp120 and human proteins, especially those participating in immune responses, highlight gp120 as a pleiotropic protein that can in different ways affect many important functions of the human immune system. Here we described some of these properties of HIV-1 gp120 that represent the main obstacle in the development of effective and safe AIDS vaccine.

Design of peptide mimetics of HIV-1 gp120 for prevention and therapy of HIV disease.

It has been reported that the C-terminus of the second conserved region (C2) of the envelope glycoprotein gp120, encompassing peptide RSANFTDNAKTIIVQLNESVEIN (NTM), is important for infectivity and neutralization of the human immunodeficiency virus type 1 (HIV-1). It was also demonstrated that human natural anti-vasoactive intestinal peptide (VIP) antibodies reactive with this gp120 region play an important role in control of HIV disease progression. The bioinformatic analysis based on the time-frequency signal processing revealed non-obvious similarities between NTM and VIP.

Cross--reactivity of the V3-speciflc antibodies with the human C1q.

It has been previously shown that the sequence similarity between a portion of the envelope glycoprotein 120 (gp120) from the human immunodeficiency virus type-1 (HIV-1) and several types of human collagen and collagen-like molecules exists. That observation led to the suggestion that the antibodies against the third hypervariable region (V3) of HIV-1 gp120 (V3-specific antibodies) might have a role in the autoimmune phenomena observed in HIV-infected persons. In this study we have examined the cross-reactivity of the V3-specific antibodies purified from sera of HIV-infected individuals, sera obtained from the rheumatoid arthritis and systemic lupus crythematosus patients, as well as from the sera of healthy volunteers with the separate chains of a subcomponent of the first component of the human complement system, Clq.

The role of passive immunization in hiv-positive patients : a case report.

An HIV-positive patient presented with pulmonary tuberculosis as her AIDS-defining diagnosis in 1993 and was effectively treated with 12 months of standard antituberculosis medications (isoniazide, rifampin, and pyrazinamide for 2 months). She received zidovudine for 6 weeks at the time of her diagnosis; however, because of patient preference, she has not received subsequent standard HIV medications (7 years). Her CD4 count at the time of diagnosis (1993) was 297/microL.

AIDS epidemic at the beginning of the third millennium: time for a new AIDS vaccine strategy.

Current expansion of AIDS pandemic significantly accelerates AIDS vaccine research resulting in development and clinical testing of several AIDS vaccine candidates. At the same time, available experimental and clinical data demonstrate that current AIDS vaccine strategy is unsuccessful resulting in development of inefficient and harmful vaccines. This overview briefly summarizes reported results which point out the requirement for moratorium on the current clinical trials of HIV-1 gp120/160 vaccines and urgent need for development of a new, efficient and safe AIDS vaccine strategy.

Anti-V3 and anti-IgG antibodies of healthy individuals share complementarity structures.

It was recently shown that antibodies reactive with a peptide from the tip of the HIV-1NY5 gp120 V3 loop (V3 peptide) are present not only in sera of HIV-positive patients but also in sera of healthy HIV-negative individuals. In the present study, we show that V3 peptide reactive antibodies are predominantly IgM in sera of HIV negative individuals and that a fraction of the IgG anti-V3 antibodies exhibit features of autoantibodies. These antibodies were purified by chromatography on IgG-sepharose columns from sera as well as from purified IgG anti-V3 antibodies.

Human immunodeficiency virus V3 peptide-reactive antibodies are present in normal HIV-negative sera.

A structural relation between consensus sequences of the portion of HIV-1 gp120 involving the V3 loop (V3 peptide) and the variable domains of human immunoglobulin members of the VH-III gene family was proposed to trigger an imbalance of the idiotypic network during the course of HIV infection. Thus, the repertoires of immunoglobulins in healthy individuals should contain antigenic determinant(s) complementary to particular V3 loop epitope(s). In this study we investigated the specific binding to the V3 peptide of antibodies present in sera of HIV-positive and of clinically normal HIV-negative subjects.

Identification of an active Chi recombinational hot spot within the HIV-1 envelope gene: consequences for development of AIDS vaccines.

Because of a sequence similarity between the HIV-1 envelope glycoprotein gp120 and the variable region of human immunoglobulins, we have suggested that the use of this protein as a vaccine component could strongly influence the host immune system, making it more vulnerable to HIV, and in the long term, accelerate disease progression in asymptomatic HIV patients. Using a chimeric primer consisting of the nucleotide sequence derived from the HIV-1 env gene coding for the second conserved region of gp120, and the highly conserved sequence derived from the human immunoglobulin gene coding for the V(H)III domain, we have identified in sera of AIDS patients HIV-1 field isolates carrying the complete and active Chi recombinational hot spot (GCTGGTGG). We have also demonstrated in vivo recombination between the HIV-1 gene coding for the central portion of the gp120 involving the V3 loop and the bacterial gene coding for the clp protease.

Further evidence for the relationship of HIV-1 gp120 V3 loops with Ig superfamily members: similarity with the putative CDR3 region of T-cell receptor delta-chains.

Twenty-five V3 loops of envelope gp 120 extracted from 30 HIV-1 isolates were compared with T-cell receptor (TCR) subunits variable (V) portions using pairwise alignments of 11-residue peptides. The results indicate that, in comparison with random sequences, the analyzed V3 loops, unlike control (unrelated) sequences, display highly significant local similarity with TCR V delta (p approximately 10(-20)). However, pattern-matching searches were performed on a much larger number of V3 loops (484).

Does the HIV-1 manipulate immune network via gp120 immunoglobulin-like domain involving V3 loop?

According to the multiple criteria used, the consensus sequences of HIV-1 gp120 and immunoglobulin heavy chain variable segment, which is more than 40 amino acids long, show structural similarities. We assume that this gp120 sequence might encode idiotopes. If this is the case then the particular idiotope-bearing gp120, either soluble or expressed in multiple form on the surface of the infected cell, can influence the immune response in idiotype(Id)-anti-Id fashion.

Immunoglobulin-like domain of HIV-1 envelope glycoprotein gp120 encodes putative internal image of some common human proteins.

By examining sequence similarity between the V3-loop of gp120 from various HIV-1 isolates and human proteins, we found that the V3 loop portion KKGIAIGPGR in strain New York 5 (HIV-1NY5) shares 70% identical residues with the collagen-like region (CLR) of human complement component C1q-A. C1q CLR was found to react with autoantibodies from several autoimmune disorders. Thus, we assumed that it would be of interest to find out the C1q reactivity with antibodies from AIDS sera.

Natural autoantibodies cross-react with a peptide derived from the second conserved region of HIV-1 envelope glycoprotein gp120.

It was recently shown that peptide NTM (RSANFTDNAKTIIVQLNESV), corresponding to residues 280-299 in the second conserved domain of HIV-1 envelope glycoprotein gp120, has spectral and sequence similarity with human vasoactive intestinal peptide, VIP (Veljkovic et al., Biochem. Biophys.