Reconstitution and characterization of antibody repertoires of HIV-1-infected "elite neutralizers"

Around 3-5% HIV-1-infected individuals develop high titers of broadly neutralizing HIV-1 antibodies (bnAbs) during chronic infection. However, monoclonal antibodies (mAbs) isolated from such "elite neutralizers" do not, in most cases, depict the serum IgGs in neutralizing the virus. We hypothesize that HIV-1-specific antibodies in infected subjects may work in a population manner in containing the virus in vivo, and in vitro reconstituted antibody repertoires of "elite neutralizers" may mimic the sera in binding and neutralizing the virus. This study aims to investigate the antibody repertoires of three such "elite neutralizers" by reconstituting the immune antibody repertories in vitro followed by a comparative study of the recombinant library IgGs with the corresponding serum IgGs. We found that the recombinant library IgGs were much weaker than the serum IgGs in binding to envelope glycoproteins (Envs) and in neutralizing the virus and inhibiting Env-mediated cell-cell fusion. However, the sorted libraries composing of HIV-1-specific neutralizing antibodies (nAbs) in the three recombinant libraries exhibited comparable binding and inhibitory activities, as well as antibody-dependent cell-mediated cytotoxicity (ADCC), to the serum IgGs. The sorted library IgGs further showed neutralization profiles which are similar to those of the serum IgGs, but they were overall less potent than the serum IgGs. The sorted library IgGs and the serum IgGs bound weakly to the resurfaced Env gp120, RSC3, and did not bind to the CD4 binding site (CD4bs) knock-out mutant, ΔRSC3. Profiling with VRC01 binding site knock-out site mutants of gp120BaL indicates that, if there are any CD4bs bnAbs in these sera, they are more likely b12-like, but not VRC01-class bnAbs. Our results suggest that HIV-1-specific Ab-expressing B cells, especially potent nAb-expressing B cells may not be rich in the B cell repertoires of "elite neutralizers", but they may be highly active in producing nAbs in vivo. In vitro reconstituted HIV-1 nAb repertoires of "elite neutralizers" may be used in passive immunization to prevent HIV-1 infection. HIV-1 vaccine immunogens may be designed to target multiple neutralizing determinants to stimulate multiple B cell populations. HIV-1-specific antibodies induced by such immunogens may work in combination or synergistically in containing the virus.