Abstract

Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.

Highlights

  • The humoral responses in individuals naturally controlling HIV1 [Virus Controllers (VCs)] include a polyclonal mix of antibodies that can mediate direct virus neutralization and antibody Fc effector functions [reviewed in [1, 2]]

  • Plasma from VCs and elite controllers (ECs) were tested for the presence of HIV-1 neutralizing antibodies with the TZM-bl nAb assay against a standardized panel of one tier 1A reference strain, one tier 1B strain, and nine tier 2 Env-pseudotyped HIV-1 viruses of multiple sub-types (Supplemental Table 1) [40] (Figure 1A)

  • Neutralization breadth was defined as the fraction of Env-pseudotyped HIV-1 viruses neutralized with an inhibitory dose 50 (ID50) titer greater than 30, while neutralization magnitude was defined as the natural logarithm of inhibitory dose 50 (ID50 titer)

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Summary

Introduction

The humoral responses in individuals naturally controlling HIV1 [Virus Controllers (VCs)] include a polyclonal mix of antibodies that can mediate direct virus neutralization and antibody Fc effector functions [reviewed in [1, 2]]. Most importantly and unlike in chronic progressors, there is evidence from studies by Freund et al [14] and Pilgrim et al [17] showing that viruses isolated from VCs are sensitive to neutralization by autologous bnAbs. Epitope mapping of the VC bNAb response indicates predominant targeting of the V3-glycan supersite of vulnerability on the HIV-1 Envelope (Env) [14, 15]. There is a need for a comprehensive epitope mapping approach that assesses the polyclonal antibody response in patients mediating virus control This approach will provide a more complete picture of the HIV-1 Envdirected immune response in the patient, and has the potential to identify novel bNAb responses targeting previously unidentified epitopes in VCs

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