Abstract
The identification of human monoclonal antibodies (mAbs) able to neutralize a broad spectrum of primary HIV-1 isolates is highly important for understanding the immune response of HIV-1 infection and developing vaccines and therapeutics. In this study, we isolated a novel human mAb termed Y498 from a phage display antibody library constructed with the PBMC samples of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity. Y498 cross-reacted with diverse Env antigens and neutralized 30% of 70 tested HIV-1 isolates. It efficiently blocked the binding of soluble CD4 to gp120 and competed with the CD4-binding site (CD4bs)-specific mAbs. By combining molecular docking and site-directed mutagenesis, the epitope of Y498 was characterized to contain three antigenic sites on gp120, including the CD4 binding loop in C3, the β23 in C4 and the β24-α5 in C5, which overlap the binding sites of CD4 and CD4bs-directed mAbs (b12, VRC01, A16). Therefore, Y498 is a novel neutralizing human mAb targeting a conformation-dependent CD4bs-based epitope, and its isolation and characterization could provide helpful information for elucidating human immune response to HIV-1 infection and designing effective vaccines and immunotherapeutics.
Highlights
human immunodeficiency virus type 1 (HIV-1) evolves with great genetic diversity, and it can be classified into distinct subtypes or clades, which pose a daunting challenge for the development of effective vaccines and immunotherapeutics; ~20% of HIV-1-infected individuals do develop antibodies that broadly neutralize HIV-1 isolates
We identified a novel HIV-1 neutralizing human antibody by panning a phage display Fab library, which was constructed with the peripheral blood mononuclear cells (PBMC) sample of a CRF07_BC-infected Chinese donor whose sera exhibited broadly neutralizing activity
Y498 was genetically characterized with the unique VH and VL sequences, a relatively long heavy chain CDR3 loop (HCDR3), and low levels of somatic hypermutaions (SHM)
Summary
HIV-1 evolves with great genetic diversity, and it can be classified into distinct subtypes or clades, which pose a daunting challenge for the development of effective vaccines and immunotherapeutics; ~20% of HIV-1-infected individuals do develop antibodies that broadly neutralize HIV-1 isolates. It is believed that the isolation and characterization of such broadly neutralizing antibodies (bnAbs) from different HIV-1-infected donors are critical for understanding human B cell-mediated immune response to HIV-1 infection and for designing immunogens that can elicit bnAbs by vaccination. A number of novel neutralizing antibodies with different specificities have been isolated and characterized by using new B cell-based sorting and screening approaches [4, 5]. Some CD4bs-specific antibodies have been isolated with lower potency and www.impactjournals.com/oncotarget breadth, such as b12, HJ16, VRC03, 1B2530, 8ANC131, A16, and DRVIA7 [1, 7, 8, 10,11,12,13]
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