Post-Immune Antibodies in HIV-1 Infection in the Context of Vaccine Development: A Variety of Biological Functions and Catalytic Activities

Abstract

Unlike many other viruses, HIV-1 is highly variable. The structure of the viral envelope changes as the infection progresses and is one of the biggest obstacles in developing an HIV-1 vaccine. HIV-1 infection can cause the production of various natural autoantibodies, including catalytic antibodies hydrolyzing DNA, myelin basic protein, histones, HIV-integrase, HIV-reverse transcriptase, β-casein, serum albumin, and some other natural substrates. Currently, there are various directions for the development of HIV-1 vaccines: stimulation of the immune response on the mucous membranes; induction of cytotoxic T cells, which lyse infected cells and hold back HIV-infection; immunization with recombinant Env proteins or vectors encoding Env; mRNA-based vaccines and some others. However, despite many attempts to develop an HIV-1 vaccine, none have been successful. Here we review the entire spectrum of antibodies found in HIV-infected patients, including neutralizing antibodies specific to various viral epitopes, as well as antibodies formed against various autoantigens, catalytic antibodies against autoantigens, and some viral proteins. We consider various promising targets for developing a vaccine that will not produce unwanted antibodies in vaccinated patients. In addition, we review common problems in the development of a vaccine against HIV-1.

Keywords: HIV; HIV-1 vaccine; IgG; antibodies; catalytic antibodies; neutralizing antibodies; vaccine; viral envelope.

Figure 1

Generation of bNAbs, which neutralize the virus through binding to viral spikes and blocking the entry of the virus into sensitive cells such as CD4⁺ T cells, is related to the evasion of virus from the immune response due to the low precision of HIV-1 reverse transcriptase and rapid generation of viral mutants. Glycan shield, immunodominant variable loops, and conformational masking of key viral epitopes protect Env from Ab-response.

Figure 2

Vulnerable targets on trimeric glycoproteins of HIV-1 spike (gp120 and gp41). Widely neutralizing Abs target the CD4 binding site on gp120, the proximal outer membrane region of gp41, the glycan shield, and epitopes in variable loops 1, 2, and 3 on gp120.

Figure 3

Several strategies are currently used to stimulate nAb responses towards bnAb generation, which consist of (A) directing of Ab response to conserved sites, for example, using fusion peptides; (B) use of mosaic or consensus antigens to overcome the viral diversity of circulating HIV-1 worldwide; (C) clonal immunogens resembling the evolution of the virus in HIV-1 infected individuals modeling natural infection; (D) targeting immunogens to putative bnAb germline progenitors, followed by immunization leading to the affinity maturation pathway to bnAb developm€; (E) selective removing of glycans to focus Ab responses to a specific site of interest, such as CD4 binding site immunogens.