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  • trk receptor br Competing interests br Introduction An effec

    2022-05-13


    Competing interests
    Introduction An effective vaccine against the Human immunodeficiency virus (HIV) is still to be created, even though many strategies have already been tried [1]. Antibodies against a vaccine antigen must be either neutralizing or inducing cellular cytotoxicity [1]. It is known that HIV virions interact with their cellular receptor (CD4) by V3 loop [1]. Since V3 loop of the gp120 protein is very variable [2], it is almost impossible to create a neutralizing antibody that will prevent the entrance of all the strains of a virus into cells. Current research on HIV vaccine development is focused on the antibody-dependent cellular cytotoxicity (ADCC) phenomenon [3]. To fight the HIV infection we really need an antibody that can bind a viral protein expressed on a cellular membrane and induce a cytotoxic reaction against infected cell [3]. Theoretically, a cell of an immune human body infected by the virus will be killed by Natural Killer cells possessing receptors for Fc regions of IgG molecules that have already bound gp120 [3]. This strategy also requires an epitope that is conserved in the most of the strains of HIV1. Recently a short peptide from the C1 region of gp120 that is conserved enough has been proposed for the vaccine development [4,5]. The fragment of a coding region encoding the chosen epitope is protected from nonsynonymous mutations better than other candidates [4]. Experimental data on the NQ21 peptide included: 1) affine chromatography with a serum of HIV1-infected person and 2) ELISA analysis of serum of 325 persons (91 of them were HIV1-infected). Antibodies able to bind the NQ21 peptide (conjugated with a resin) were found in sera of HIV1-infected persons [5]. In addition, it was confirmed that 80% of HIV1-infected persons have these antibodies, in contrast to uninfected people who have no such trk receptor [5]. According to recent paper on 3D structures of a core of gp120 with antibodies inducing cytotoxicity, the fragment corresponding to the NQ21 peptide (residues 94–114) is one of the areas that are bound by such antibodies [6]. Indeed, three 3D structures studied in Ref. [6] had three amino acid residues of the NQ21 peptide (Glu106, Asp107 and Asp113) that were found to form hydrogen bonds and ionic contacts with antibodies demonstrating ADCC. The epitopes of C1 region of gp120 are known to be CD4-inducible [7]. These epitopes are exposed when the viral envelope trimers (complexes of three gp120 and three gp41 proteins) bind cellular receptor CD4 and survive on freshly infected cell surfaces for extended periods of postinfection time, as well as on persistently infected cells [7]. What is more the antibodies against C1 region provoking ADCC are found in controllers of HIV1 infection. According to [7] Gln103, Glu106, and Asp107 amino acid residues are included in the binding area for those antibodies. To develop a high titer of such antibodies one cannot use the complete monomeric gp120 protein. Highly immunogenic epitopes of gp120 are characterized by a great variability, while conserved ones are less immunogenic [4]. The NQ21 peptide has 21 amino acid residues. 19 of them are used in more than 95% of HIV1 sequences [5]. In contrast, just 15 of 38 amino acid residues of the highly immunogenic V3 loop of gp120 are used in the same percentage of HIV1 sequences [5]. Supposedly, it takes many years for some HIV1-infected persons to develop relatively effective neutralizing antibodies trk receptor [8]. Analysis of 3D-structures of antibodies bound to gp120 from one of such controllers showed that they are in contact with the residues included in the NQ21 peptide: Lys97, Glu102, Thr106, Ile109 [8]. One of the newly suggested strategies is to construct a core of gp120 (without variable highly immunogenic regions) and immunize just with such a core aiming at increase of the titer of antibodies inducing cytotoxicity [3]. The acceptance of this idea is very encouraging to continue the efforts to develop the vaccine based on the short synthetic antigen proposed in Refs. [4,5].