Increased breadth of HIV-1 neutralization achieved by diverse antibody clones each with limited neutralization breadth

Abstract

Broadly neutralizing antibodies (bNAbs) are rarely elicited by current human immunodeficiency virus type 1 (HIV-1) vaccine designs, but the presence of bNAbs in naturally infected individuals may be associated with high plasma viral loads, suggesting that the magnitude, duration, and diversity of viral exposure may contribute to the development of bNAbs. Here, we report the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. In both subjects, we identified collections of mAbs that exhibited specificity only to a few autologous envelopes (Envs), with some mAbs exhibiting specificity only to a subset of Envs within the quasispecies of a particular sample at one time point. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. None of the individual neutralizing mAbs recovered exhibited the cumulative breadth of neutralization present in the serum of the subjects. Surprisingly, however, the activity of polyclonal mixtures comprising individual mAbs that each possessed limited neutralizing activity, could achieve increased breadth of neutralizing activity against autologous isolates. While a single broadly neutralizing antibody targeting one epitope can mediate neutralization breadth, the findings presented here suggest that a cooperative polyclonal process mediated by diverse antibodies with more limited breadth targeting multiple epitopes also can achieve neutralization breadth against HIV-1.

Functional HIV-1/HCV cross-reactive antibodies isolated from a chronically co-infected donor

“… 27 , 28 Monoclonal antibody discovery efforts in this donor failed to identify any broadly neutralizing antibodies, instead attributing the observed serum breadth to diverse antibody lineages with complementary patterns of neutralizing activity. 29 Given the ability of LIBRA-seq to screen tens of thousands of B cells against a large panel of diverse antigens, including those from unrelated pathogens, we sought to apply this technology to HIV-1/HCV co-infected donor VC10014. The application of LIBRA-seq provides an opportunity to interrogate the antibody repertoire against the complex setting of chronic exposure to diverse and constantly evolving antigens.…”

CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques

“…The VC10014 immunogen platform has consistently demonstrated the induction of Tier 2 heterologous NAbs ( 20 , 21 , 39 ). Although modest, the Imm group showed a trend toward enhanced protection from repeated heterologous challenge, as well as conferring decreased viral burden upon infection.…”

Pathways towards human immunodeficiency virus elimination

“…They target conserved epitopes of the HIV-1 envelope, enabling them to circumvent the frequent viral mutations seen during low-level viral growth. Isolation, cloning, and single-cell antibody techniques have enabled effective bnAb discovery [55]. BnAbs are produced about two and half years after initial viral infection and are linked to slow disease progression.…”