Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir.
Animals
Antibodies, Neutralizing
/ immunology
Antibody-Dependent Cell Cytotoxicity
Antiviral Agents
/ therapeutic use
CD4 Antigens
/ chemistry
CD4-Positive T-Lymphocytes
/ immunology
Cell Line
Epitopes
/ immunology
Female
Glycoproteins
/ chemistry
HEK293 Cells
HIV Infections
/ drug therapy
HIV-1
/ chemistry
Humans
Immunoglobulin Fc Fragments
/ immunology
Killer Cells, Natural
/ immunology
Male
Mice
Mice, SCID
Models, Animal
Protein Conformation
Virus Replication
/ drug effects
env Gene Products, Human Immunodeficiency Virus
/ chemistry
CD4i Abs
HIV-1
NK cell
SRG-15
State 2A
antibody-dependent cellular cytotoxicity
envelope glycoprotein
humanized mice
Journal
Cell host & microbe
ISSN: 1934-6069
Titre abrégé: Cell Host Microbe
Pays: United States
ID NLM: 101302316
Informations de publication
Date de publication:
09 Jun 2021
09 Jun 2021
Historique:
received:
18
08
2020
revised:
01
02
2021
accepted:
20
04
2021
pubmed:
22
5
2021
medline:
26
10
2021
entrez:
21
5
2021
Statut:
ppublish
Résumé
Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.
Identifiants
pubmed: 34019804
pii: S1931-3128(21)00190-6
doi: 10.1016/j.chom.2021.04.014
pmc: PMC8214472
mid: NIHMS1708265
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
Antiviral Agents
0
CD4 Antigens
0
Epitopes
0
Glycoproteins
0
Immunoglobulin Fc Fragments
0
env Gene Products, Human Immunodeficiency Virus
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
904-916.e6Subventions
Organisme : NIAID NIH HHS
ID : UM1 AI126620
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148379
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI150471
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129769
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150322
Pays : United States
Organisme : NIGMS NIH HHS
ID : P01 GM056550
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI162646
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI131251
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI150741
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150464
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI116274
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI122384
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145164
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI141572
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI124982
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI050529
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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