Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge.
Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expresse...
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2018-12-01
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doaj-7eecd2e6b1874777aea557531aa773a22021-04-21T17:11:39ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742018-12-011412e100739510.1371/journal.ppat.1007395Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge.Hugh C WellesMadeleine F JenneweinRosemarie D MasonSandeep NarpalaLingshu WangCheng ChengYi ZhangJohn-Paul ToddJeffrey D LifsonAlejandro B BalazsGalit AlterAdrian B McDermottJohn R MascolaMario RoedererGene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization.https://doi.org/10.1371/journal.ppat.1007395 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hugh C Welles Madeleine F Jennewein Rosemarie D Mason Sandeep Narpala Lingshu Wang Cheng Cheng Yi Zhang John-Paul Todd Jeffrey D Lifson Alejandro B Balazs Galit Alter Adrian B McDermott John R Mascola Mario Roederer |
spellingShingle |
Hugh C Welles Madeleine F Jennewein Rosemarie D Mason Sandeep Narpala Lingshu Wang Cheng Cheng Yi Zhang John-Paul Todd Jeffrey D Lifson Alejandro B Balazs Galit Alter Adrian B McDermott John R Mascola Mario Roederer Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. PLoS Pathogens |
author_facet |
Hugh C Welles Madeleine F Jennewein Rosemarie D Mason Sandeep Narpala Lingshu Wang Cheng Cheng Yi Zhang John-Paul Todd Jeffrey D Lifson Alejandro B Balazs Galit Alter Adrian B McDermott John R Mascola Mario Roederer |
author_sort |
Hugh C Welles |
title |
Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. |
title_short |
Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. |
title_full |
Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. |
title_fullStr |
Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. |
title_full_unstemmed |
Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. |
title_sort |
vectored delivery of anti-siv envelope targeting mab via aav8 protects rhesus macaques from repeated limiting dose intrarectal swarm sivsme660 challenge. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2018-12-01 |
description |
Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization. |
url |
https://doi.org/10.1371/journal.ppat.1007395 |
work_keys_str_mv |
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