Cargando…

The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat

The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targ...

Descripción completa

Detalles Bibliográficos
Autores principales: Montefiori, David C., Filsinger Interrante, Maria V., Bell, Benjamin N., Rubio, Adonis A., Joyce, Joseph G., Shiver, John W., LaBranche, Celia C., Kim, Peter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826338/
https://www.ncbi.nlm.nih.gov/pubmed/33431684
http://dx.doi.org/10.1073/pnas.2018027118
_version_ 1783640514888728576
author Montefiori, David C.
Filsinger Interrante, Maria V.
Bell, Benjamin N.
Rubio, Adonis A.
Joyce, Joseph G.
Shiver, John W.
LaBranche, Celia C.
Kim, Peter S.
author_facet Montefiori, David C.
Filsinger Interrante, Maria V.
Bell, Benjamin N.
Rubio, Adonis A.
Joyce, Joseph G.
Shiver, John W.
LaBranche, Celia C.
Kim, Peter S.
author_sort Montefiori, David C.
collection PubMed
description The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1–infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1–infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)(3) neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.
format Online
Article
Text
id pubmed-7826338
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-78263382021-01-28 The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat Montefiori, David C. Filsinger Interrante, Maria V. Bell, Benjamin N. Rubio, Adonis A. Joyce, Joseph G. Shiver, John W. LaBranche, Celia C. Kim, Peter S. Proc Natl Acad Sci U S A Biological Sciences The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1–infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1–infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)(3) neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine. National Academy of Sciences 2021-01-19 2021-01-11 /pmc/articles/PMC7826338/ /pubmed/33431684 http://dx.doi.org/10.1073/pnas.2018027118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Montefiori, David C.
Filsinger Interrante, Maria V.
Bell, Benjamin N.
Rubio, Adonis A.
Joyce, Joseph G.
Shiver, John W.
LaBranche, Celia C.
Kim, Peter S.
The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title_full The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title_fullStr The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title_full_unstemmed The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title_short The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
title_sort high-affinity immunoglobulin receptor fcγri potentiates hiv-1 neutralization via antibodies against the gp41 n-heptad repeat
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826338/
https://www.ncbi.nlm.nih.gov/pubmed/33431684
http://dx.doi.org/10.1073/pnas.2018027118
work_keys_str_mv AT montefioridavidc thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT filsingerinterrantemariav thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT bellbenjaminn thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT rubioadonisa thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT joycejosephg thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT shiverjohnw thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT labrancheceliac thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT kimpeters thehighaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT montefioridavidc highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT filsingerinterrantemariav highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT bellbenjaminn highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT rubioadonisa highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT joycejosephg highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT shiverjohnw highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT labrancheceliac highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat
AT kimpeters highaffinityimmunoglobulinreceptorfcgripotentiateshiv1neutralizationviaantibodiesagainstthegp41nheptadrepeat