Activation and lysis of human CD4 cells latently infected with HIV-1.
The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals.
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Amarendra
A
Pegu
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Mangaiarkarasi
M
Asokan
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Lan
L
Wu
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Keyun
K
Wang
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Jason
J
Hataye
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Joseph P
JP
Casazza
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Xiaoti
X
Guo
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Wei
W
Shi
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Ivelin
I
Georgiev
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Tongqing
T
Zhou
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Xuejun
X
Chen
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Sijy
S
O'Dell
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
John-Paul
JP
Todd
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Peter D
PD
Kwong
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Srinivas S
SS
Rao
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Zhi-yong
ZY
Yang
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Richard A
RA
Koup
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
John R
JR
Mascola
Vaccine Research Center National Institute for Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005 40 Convent Drive, Bethesda, Maryland 20892-3005, USA.
Gary J
GJ
Nabel
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D057134:Antibodies, Neutralizing; D017252:CD3 Complex; D016207:Cytokines; D007155:Immunologic Factors; D011948:Receptors, Antigen, T-Cell; D054299:env Gene Products, Human Immunodeficiency Virus