HIV-1 Env-specific IgA/IgG Ratio Is Related to Antibody Dependent Cellular Cytotoxicity (ADCC) Responses Observed during Acute/Early HIV Infection

ABSTRACT Antibodies (Abs) specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (C1/C2) were induced in the RV144 vaccine trial, where antibody-dependent cellular cytotoxicity (ADCC) correlated with reduced risk of HIV-1 infection. We combined X-ray crystallography and fluorescence resonance energy transfer-fluorescence correlation spectroscopy to describe the molecular basis for epitopes of seven RV144 Abs and compared them to A32 and C11, C1/C2 Abs induced in HIV infection. Our data indicate that most vaccine Abs recognize the 7-stranded β-sandwich of gp120, a unique hybrid epitope bridging A32 and C11 binding sites. Although primarily directed at the 7-stranded β-sandwich, some accommodate the gp120 N terminus in C11-bound 8-stranded conformation and therefore recognize a broader range of CD4-triggered Env conformations. Our data also suggest that Abs of RV144 and RV305, the RV144 follow-up study, although likely initially induced by the ALVAC-HIV prime encoding full-length gp120, matured through boosting with truncated AIDSVAX gp120 variants. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) correlated with a reduced risk of infection from HIV-1 in the RV144 vaccine trial, the only HIV-1 vaccine trial to date to show any efficacy. Antibodies specific for CD4-induced envelope (Env) epitopes within constant region 1 and 2 (cluster A region) were induced in the RV144 trial and their ADCC activities were implicated in the vaccine efficacy. We present structural analyses of the antigen epitope targets of several RV144 antibodies specific for this region and C11, an antibody induced in natural infection, to show what the differences are in epitope specificities, mechanism of antigen recognition, and ADCC activities of antibodies induced by vaccination and during the course of HIV infection. Our data suggest that the truncated AIDSVAX gp120 variants used in the boost of the RV144 regimen may have shaped the vaccine response to this region, which could also have contributed to vaccine efficacy.

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Antibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected Subjects

mBio ◽

10.1128/mbio.02690-19 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 3

Author(s):

Franck P. Dupuy ◽

Sanket Kant ◽

Alexandre Barbé ◽

Jean-Pierre Routy ◽

Julie Bruneau ◽

...

Keyword(s):

Hiv Infection ◽

Cell Types ◽

Target Cells ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Adcc Assay ◽

Cd4 Binding Site ◽

Infected Cells ◽

Bystander Cells ◽

Hiv 1

ABSTRACT Measuring Envelope (Env)-specific antibody (Ab)-dependent cellular cytotoxicity (ADCC)-competent Abs in HIV+ plasma is challenging because Env displays distinctive epitopes when present in a native closed trimeric conformation on infected cells or in a CD4-bound conformation on uninfected bystander cells. We developed an ADCC model which distinguishes Env-specific ADCC-competent Abs based on their capacity to eliminate infected, bystander, or Env rgp120-coated cells as a surrogate for shed gp120 on bystander cells. A panel of monoclonal Abs (MAbs), used to opsonize these target cells, showed that infected cells were preferentially recognized/eliminated by MAbs to CD4 binding site, V3 loop, and viral spike epitopes whereas bystander/coated cells were preferentially recognized/eliminated by Abs to CD4-induced (CD4i) epitopes. In HIV-positive (HIV+) plasma, Env-specific Abs recognized and supported ADCC of infected cells, though a majority were directed toward CD4i epitopes on bystander cells. For ADCC activity to be effective in HIV control, ADCC-competent Abs need to target genuinely infected cells. IMPORTANCE HIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which simultaneously quantifies the killing activity of Env-specific Abs on both infected and uninfected bystander cells, we observed that only a minority of Env-specific Abs in HIV+ plasma mediated ADCC of genuinely HIV-infected cells displaying Env in its native closed conformation. This assay can be used for the development of vaccine strategies aimed at eliciting Env-specific Ab responses capable of controlling HIV infection.

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Cross-Reactive Antibodies With the Capacity to Mediate HIV-1 Envelope Glycoprotein–Targeted Antibody-Dependent Cellular Cytotoxicity Identified in HIV-2–Infected Individuals

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz001 ◽

2019 ◽

Vol 219 (11) ◽

pp. 1749-1754 ◽

Cited By ~ 3

Author(s):

Ingrid Karlsson ◽

Jeanette Linnea Tingstedt ◽

Gülşen Özkaya Şahin ◽

Mikkel Hansen ◽

Zsofia Szojka ◽

...

Keyword(s):

Envelope Glycoprotein ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Hiv 1

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Immunization with Clinical HIV-1 Env Proteins Induces Broad Antibody Dependent Cellular Cytotoxicity–Mediating Antibodies in a Rabbit Vaccination Model

AIDS Research and Human Retroviruses ◽

10.1089/aid.2017.0140 ◽

2018 ◽

Vol 34 (2) ◽

pp. 206-217 ◽

Cited By ~ 2

Author(s):

Ingrid Karlsson ◽

Marie Borggren ◽

Sanne Skov Jensen ◽

Leo Heyndrickx ◽

Guillaume Stewart-Jones ◽

...

Keyword(s):

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Hiv 1

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HIV-1-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC)

HIV Protocols ◽

10.1385/0-89603-369-4:373 ◽

2003 ◽

pp. 373-382 ◽

Cited By ~ 1

Author(s):

Josephine H. Cox

Keyword(s):

Specific Antibody ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Hiv 1

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Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/macEnvelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

mBio ◽

10.1128/mbio.01255-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 6

Author(s):

Benjamin von Bredow ◽

Raiees Andrabi ◽

Michael Grunst ◽

Andres G. Grandea ◽

Khoa Le ◽

...

Keyword(s):

Binding Affinity ◽

Specific Antibody ◽

Neutralizing Antibody ◽

Glycosylation Site ◽

Antibody Binding ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Broadly Neutralizing Antibody ◽

Infected Cells ◽

Hiv 1

ABSTRACTAs a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.

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Antibody-Induced Internalization of HIV-1 Env Proteins Limits Surface Expression of the Closed Conformation of Env

Journal of Virology ◽

10.1128/jvi.00293-19 ◽

2019 ◽

Vol 93 (11) ◽

Cited By ~ 10

Author(s):

Sai Priya Anand ◽

Jonathan R. Grover ◽

William D. Tolbert ◽

Jérémie Prévost ◽

Jonathan Richard ◽

...

Keyword(s):

Immune Responses ◽

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Surface Expression ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Broadly Neutralizing Antibodies ◽

Closed Conformation ◽

Infected Cells ◽

Hiv 1

ABSTRACT To minimize immune responses against infected cells, HIV-1 limits the surface expression of its envelope glycoprotein (Env). Here, we demonstrate that this mechanism is specific for the Env conformation and affects the efficiency of antibody-dependent cellular cytotoxicity (ADCC). Using flow cytometry and confocal microscopy, we show that broadly neutralizing antibodies (bNAbs) targeting the “closed” conformation of Env induce its internalization from the surface. In contrast, non-neutralizing antibodies (nNAbs) are displayed on the cell surface for prolonged period of times. The bNAb-induced Env internalization can be decreased by blocking dynamin function, which translates into higher susceptibilities of infected cells to ADCC. Our results suggest that antibody-mediated Env internalization is a mechanism used by HIV-1 to evade immune responses against the “closed” conformation of Env expressed on HIV-1-infected cells. IMPORTANCE HIV-1 has evolved to acquire several strategies to limit the exposure of its envelope glycoproteins (Env) on the surface of infected cells. In this study, we show that antibody-induced Env internalization is conformation specific and reduces the susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). Thus, a better understanding of this mechanism might help develop antibodies with improved capacities to mediate ADCC.

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Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial preferentially use the VH1 gene family

Retrovirology ◽

10.1186/1742-4690-9-s2-p78 ◽

2012 ◽

Vol 9 (S2) ◽

Author(s):

M Bonsignori ◽

J Pollara ◽

MA Moody ◽

TB Kepler ◽

X Chen ◽

...

Keyword(s):

Gene Family ◽

Vaccine Efficacy ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Efficacy Trial ◽

Hiv 1

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Antiphosphatidylserine antibodies in human immunodeficiency virus-1 patients with evidence of T-cell apoptosis and mediate antibody- dependent cellular cytotoxicity [see comments]

Blood ◽

10.1182/blood.v87.12.5185.bloodjournal87125185 ◽

1996 ◽

Vol 87 (12) ◽

pp. 5185-5195 ◽

Cited By ~ 28

Author(s):

F Silvestris ◽

MA Frassanito ◽

P Cafforio ◽

D Potenza ◽

M Di Loreto ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Cell Apoptosis ◽

Clinical Feature ◽

Enzyme Linked Immunosorbent Assay ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

T Cell Apoptosis ◽

Immunodeficiency Virus ◽

Hiv 1

Serum reactivities to a panel of phospholipid antigens, including cardiolipin (CL), phosphatidylserine (PS), sphingomyelin, phosphatidylcholine, and phosphatidylethanolamine, were measured by enzyme-linked immunosorbent assay in 196 human immunodeficiency virus- l+ (HIV-1+) patients with CDC II to IVC clinical disease. Significant levels of IgG to CL, PS, or both were observed in 23 patients lacking evidence of thrombophilic events or any peculiar clinical feature of HIV-1 infection. Fluorescence-activated cell sorting analyses showed that in vitro apoptosis of T cells was increased in patients with high serum anti-PS IgG, whereas the overexpression of Fas/Apo-1 marker was detected in all patients regardless of their antiphospholipid reactivities. Macrophages from patients with significant titers of anti- PS IgG antibodies were not activated by the presence of apoptotic CEM lymphoblasts or by purified anti-PS IgG from the same patients. By contrast, these antibodies greatly improved the effector functions of autologous macrophages in antibody-dependent cellular cytotoxicity (ADCC) assays using 51Cr-labeled CEM cells, whereas polyspecific IgG were unable to induce an equivalent cytotoxicity in all instances. An increasing effect on ADCC was also observed in tests using macrophages from healthy controls to CEM coated with anti-PS IgG. These results support a potential correlation of anti-PS specificity with T-cell apoptosis in HIV-1 infection. Because PS is exteriorized by apoptotic lymphocytes, its persistence may stimulate antibodies which cooperate with macrophages in the clearance of dead cells by an enhanced ADCC mechanism. This interpretation could explain the absence of thrombophilia in HIV-1+ patients with serum elevations of antiphospholipid reactivities.

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