An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

The effect of anti-HIV-1 antibodies on complement activation at the surface of infected cells remains partly understood. Here, we show that a subset of anti-Envelope (Env) broadly neutralizing antibodies (bNAbs), targeting the CD4 binding site and the V3 loop, triggers C3 deposition and complement-dependent cytotoxicity (CDC) on Raji cells engineered to express high surface levels of HIV-1 Env. Primary CD4 T cells infected with laboratory-adapted or primary HIV-1 strains and treated with bNAbs are susceptible to C3 deposition but not to rapid CDC. The cellular protein CD59 and viral proteins Vpu and Nef protect infected cells from CDC mediated by bNAbs or by polyclonal IgGs from HIV-positive individuals. However, complement deposition accelerates the disappearance of infected cells within a few days of culture. Altogether, our results uncover the contribution of complement to the antiviral activity of anti-HIV-1 bNAbs.

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“…After bound to the receptor CD4) [53][54][55]. The numbers indicate the % of bNAb + cells among infected (Gag + ) cells.…”

Section: A Primary Cd4 T Cells Were Infected With Wt or Dvpu Hiv-1 (Nmentioning

confidence: 99%

“…n = 6 donors of CD4 T cells. bound to the receptor CD4) [53][54][55]. The viral protein Nef is an infectivity factor that down-regulates various cellular proteins from the surface of infected cells, including CD4, MHC-I, and SERINC3/5 [56].…”

Section: Polyclonal Anti-hiv Antibodies Activate the Complement At Thmentioning

confidence: 99%

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

et al. 2019

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“…Most likely this feature allows DH677.3 to recognize a broader range of Env targets, emerging in both the early (when A32 epitope becomes available) and late stage (when C11 epitope becomes available) of the viral entry process. Identification of a stage 2A of the HIV-1 Env expressed on the surface of infected cells in presence of the CD4 molecule or CD4 mimetics reiterate the importance of targeting these epitopes by vaccine induced responses as detected in our assays [23]. In addition, a model of DH677.3 in complex with gp120 antigen bound to a CD4 of a target/infected cell confirms that the recognition site and angle of approach position the DH677.3 IgG for easy access for effector cell recognition and Fc-effector complex formation ( Fig 4A ).…”

Section: Discussionmentioning

confidence: 86%

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

Easterhoff

Pollara

Luo

et al. 2019

Preprint

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Significance 26Over one million people become infected with HIV-1 each year making the development 27 of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human 28 HIV-1 vaccine-regimen is the only HIV-1 clinical trial to date to demonstrate vaccine- 29 efficacy. An area of focus has been on identifying ways by which to improve upon 30 RV144 vaccine-efficacy. The RV305 HIV-1 vaccine-regimen was a follow-up boost of 31 RV144 vaccine-recipients that occurred 6-8 years after the conclusion of RV144. Our 32 2 studies focused on the effect of delayed boosting in humans on the vaccine-induced 33 antibody repertoire. It was found that boosting with a HIV-1 Env vaccine increased 34 antibody-mediated effector function potency and breadth. 35Abstract 36 Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One 37 strategy is to induce non-neutralizing antibodies that kill virus-infected cells as these 38 antibody specificities have been implicated in slowing HIV-1 disease progression and in 39 protection. HIV-1 Env constant region 1 and 2 (C1C2) antibodies frequently contain 40 potent antibody dependent cellular cytotoxicity (ADCC) making them a vaccine target. 41Here we explore the effect of delayed and repetitive boosting of RV144 vaccinee 42 recipients with ALVAC/AIDSVAX B/E on the C1C2-specific antibody repertoire. It was 43 found that boosting increased clonal lineage specific ADCC breadth and potency. A 44 ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-45 specific antibody showed that it bound a highly conserved Env gp120 epitope. Thus, 46 rationally designed boosting strategies to affinity mature these type of IgG C1C2-47 specific antibody responses may be one method by which to make an improved HIV 48 vaccine with higher efficacy than seen in the RV144 trial. 49 INTRODUCTION 50CD4-inducible (CD4i) epitopes within HIV-1 envelope (Env) constant regions 1 and 51 2 (C1C2) are targets for antibodies that mediate antibody dependent cellular cytotoxicity 52 (ADCC) [1]. C1C2-specific antibody epitopes have been termed Cluster A [1] and defined 53 by two Env-targeted monoclonal antibodies (mAbs), A32 [2] and C11 [1]. Structural 54 analyses of antigen complexes formed by A32, A32-like [3-5] and C11-like antibodies [6] 55 3 indicate that these antibodies bind distinct Env epitopes. The A32 epitope involves a 56 discontinuous sequence within layers 1 and 2 of the inner domain [4, 5] while the C11 57 epitope maps to the inner domain eight-stranded β sandwich [6]. Importantly, both 58 antibodies are non-neutralizing for tier 2 HIV strains, but are capable of broad and potent 59 ADCC [1, 2]. 60 The secondary analysis of HIV-1 infection risk in RV114 (NCT00223080) 61 indicated that ADCC in the presence of low anti-Env IgA responses correlated with 62 decreased HIV-1 acquisition [7]. While antibodies representative of the Env variable 63 region 2 (V2) response inversely correlated with HIV-1 acquisition [7], we previously 64 demo...

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“…Finzi HIV-1 Env: Joe Doupe Lecture vivo settings. The CD4mc have been shown to sensitize HIV-1-infected cells to ADCC mediated by antibodies present in sera, cervicovaginal fluids and breast milk from HIV-1-infected individuals [22][23][24][25][26][27][28], as well as sera from gp120-vaccinated non-human primates [29,30]. This strategy was also shown to work against primary CD4 T cells isolated from HIV+ individuals using their own (autologous) sera [27,28].…”

Section: Small Cd4-mimetic Compounds (Cd4mc) Expose Env Cd4i Epitopesmentioning

confidence: 99%

“…Therefore, ADCC responses mediated by cluster A antibodies in HIV+ sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells [22]. It was recently shown that CD4mc, anti-CoRBS and anti-cluster A antibodies stabilize a new, ADCC-vulnerable, asymmetric state 2A conformation [23]. Whether stabilizing this conformation in vivo has an impact on the size of the viral reservoir or disease progression remains to be evaluated.…”

Section: Sequential Opening Of Env Is Required To Expose Adcc-mediatimentioning

confidence: 99%

Exposing HIV-1 Env: Implications for therapeutic strategies

Finzi

2019

CIM

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The human immunodeficiency virus (HIV-1) envelope glycoprotein trimer (Env) is exposed on the surfaces of both virions and infected cells. Thus, Env is the principal target for neutralizing antibodies and antibodies able to mediate antibodydependent cellular cytotoxicity (ADCC). The HIV-1 Env is a flexible molecule known to exist in at least three different conformational states: states 1, 2 and 3. Before interacting with the primary receptor, CD4, Env preferentially adopts a compact, "closed" conformation (state 1) that is largely antibody-resistant. The CD4 binding "opens" Env increasing the vulnerability of infected cells to ADCC mediated by non-neutralizing antibodies, as these easily-elicited antibodies preferentially recognize epitopes exposed in the open conformational states (states 2/3). These antibodies include the anti-coreceptor binding site and the anti-cluster A families of antibodies that, in combination with small CD4-mimetic compounds, stabilize a new asymmetric Env conformation (state 2A) that is vulnerable to ADCC. Approaches aimed at stabilizing this "open" conformation represent new interventional approaches to fight HIV-1 infection.

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An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

Cited by 94 publications

References 56 publications

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

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

Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

Exposing HIV-1 Env: Implications for therapeutic strategies

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