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

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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Faculty Opinions recommendation of Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/mac Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736126194.793562589 ◽

2019 ◽

Author(s):

Noah Sather

Keyword(s):

Binding Affinity ◽

Specific Antibody ◽

Envelope Glycoprotein ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Hiv 1

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The role of HIV-specific antibody-dependent cellular cytotoxicity in HIV prevention and the influence of the HIV-1 Vpu protein

AIDS ◽

10.1097/qad.0000000000000523 ◽

2015 ◽

Vol 29 (2) ◽

pp. 137-144 ◽

Cited By ~ 25

Author(s):

Marit Kramski ◽

Ivan Stratov ◽

Stephen J. Kent

Keyword(s):

Hiv Prevention ◽

Specific Antibody ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Hiv 1

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Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency

Journal of Virology ◽

10.1128/jvi.01120-19 ◽

2019 ◽

Vol 94 (4) ◽

Cited By ~ 4

Author(s):

David Easterhoff ◽

Justin Pollara ◽

Kan Luo ◽

William D. Tolbert ◽

Brianna Young ◽

...

Keyword(s):

Specific Antibody ◽

Vaccine Efficacy ◽

Vaccine Development ◽

Constant Region ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Vaccine Regimen ◽

Protective Antibodies ◽

Hiv 1 ◽

Rv144 Vaccine

ABSTRACT Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial. IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth.

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

10.1101/632844 ◽

2019 ◽

Cited By ~ 2

Author(s):

David Easterhoff ◽

Justin Pollara ◽

Kan Luo ◽

William D. Tolbert ◽

Brianna Young ◽

...

Keyword(s):

Specific Antibody ◽

Vaccine Efficacy ◽

Vaccine Development ◽

Antibody Repertoire ◽

Constant Region ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Vaccine Regimen ◽

Hiv 1 ◽

Rv144 Vaccine

AbstractInduction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce non-neutralizing antibodies that kill virus-infected cells as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) antibodies frequently contain potent antibody dependent cellular cytotoxicity (ADCC) making them a vaccine target. Here we explore the effect of delayed and repetitive boosting of RV144 vaccinee recipients with ALVAC/AIDSVAX B/E on the C1C2-specific antibody repertoire. It was found that boosting increased clonal lineage specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific antibody showed that it bound a highly conserved Env gp120 epitope. Thus, rationally designed boosting strategies to affinity mature these type of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than seen in the RV144 trial.SignificanceOver one million people become infected with HIV-1 each year making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine-regimen is the only HIV-1 clinical trial to date to demonstrate vaccine-efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine-efficacy. The RV305 HIV-1 vaccine-regimen was a follow-up boost of RV144 vaccine-recipients that occurred 6-8 years after the conclusion of RV144. Our studies focused on the effect of delayed boosting in humans on the vaccine-induced antibody repertoire. It was found that boosting with a HIV-1 Env vaccine increased antibody-mediated effector function potency and breadth.

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