Comprehensive Cross-Clade Characterization of Antibody-Mediated Recognition, Complement-Mediated Lysis, and Cell-Mediated Cytotoxicity of HIV-1 Envelope-Specific Antibodies toward Eradication of the HIV-1 Reservoir

Abstract

Immunotherapy with passive administration of broadly neutralizing HIV-1 envelope-specific antibodies (bnAbs) in the setting of established infection in vivo has yielded mixed results. The contribution of different antibodies toward the direct elimination of infected cells is poorly understood. In this study, we determined the ability of 12 well-characterized anti-HIV-1 neutralizing antibodies to recognize and eliminate primary CD4 T cells infected with HIV-1 belonging to clades A, B, C, and D, via antibody-dependent complement-mediated lysis (ADCML) and antibody-dependent cell-mediated cytotoxicity (ADCC), in vitro. We further tested unique combinations of these antibodies to determine the optimal antibody cocktails to be tested in future clinical trials. We report that antibody binding to infected CD4 T cells is highly variable and correlates with ADCML and ADCC processes. Particularly, antibodies targeting the envelope glycan shield (2G12) and V1/V2 site (PG9, PG16, and PGT145) are best at recognizing HIV-1-infected CD4 T cells. However, only PG9 and PG16 and their combinations with other bnAbs sufficiently induced the elimination of HIV-1-infected CD4 T cells by ADCML, ADCC, or both. Notably, CD4 binding site antibodies VRC01, 3BNC117, and NIH45-46 G54W did not exhibit recognition of infected cells and were unable to induce their killing. Future trials geared toward the development of a cure for HIV/AIDS should incorporate V1/V2 antibodies for maximal clearance of infected cells. With the use of only primary immune cells, we conducted a comprehensive cross-clade physiological analysis to aid the direction of antibodies as therapeutics toward the development of a cure for HIV/AIDS. IMPORTANCE Several antibodies capable of neutralizing the majority of circulating HIV-1 strains have been identified to date and have been shown to prevent infection in animal models. However, the use of combinations of such broadly neutralizing antibodies (bnAbs) for the treatment and eradication of HIV-1 in infected humans remains uncertain. In this study, we tested the ability of bnAbs to directly recognize and eliminate primary human CD4 T cells infected with diverse HIV-1 strains representative of the global epidemic by antibody-dependent pathways. We also tested several combinations of bnAbs in our assays in order to maximize the clearance of infected cells. We show that the ability of bnAbs to identify and kill infected cells is highly variable and that only a few of them are able to exert this

Anti‐HIV‐1 antibodies trigger non‐lytic complement deposition on infected cells

“…Cells that have captured viral material [42,43], or at an early stage of infection, have been proposed to be the main target of CDC [35]. Anti-V1/V2 glycans [35] and anti-V3 antibodies [36,44] were suggested to be better CDC inducers than other antibodies. Yet, the impact of the most recent bNAbs on the complement pathway has not been thoroughly analyzed.…”

Randomized Clinical Trial to Assess the Impact of the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01 on HIV-1 Persistence in Individuals on Effective ART

“…The capacity for antibody binding to infected CD4 T cells varies among the bnMAbs. In vitro experiments performed by Mujib et al and others have shown low levels of infected cell binding and ADCC for CD4 binding site antibodies, including VRC01 and 3BNC117 [ 10 , 36 ]. The clearance of infected cells by antibody requires the expression of envelope on the cell surface; however, only a small fraction of HIV-infected cells in blood express unspliced HIV-1 RNA [ 37 ].…”

Targeting the Latent Reservoir for HIV-1

“…The authors concluded that defective proviruses may be preferentially targeted by CTLs, perhaps due to mutations or deletions in the HIV-1 nef gene (Bruner et al 2016), whose protein product downregulates MHC-I (Huang et al 2018). If so, pharmacologic blockade of Nef may improve CTL killing of cells harboring intact proviruses and therefore reduce the reservoir (Mujib et al 2017a). …”