Activation and lysis of human CD4 cells latently infected with HIV-1.

Abstract

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.

• Authors: Amarendra Pegu, Mangaiarkarasi Asokan, Lan Wu, Keyun Wang, Jason Hataye, Joseph P Casazza, Xiaoti Guo, Wei Shi, Ivelin Georgiev, Tongqing Zhou, Xuejun Chen, Sijy O'Dell, John-Paul Todd, Peter D Kwong, Srinivas S Rao, Zhi-yong Yang, Richard A Koup, John R Mascola, Gary J Nabel
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 8447 (Oct 20 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26485194 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antibodies, Neutralizing
• CD3 Complex
• Cytokines
• Immunologic Factors
• Receptors, Antigen, T-Cell
• env Gene Products, Human Immunodeficiency Virus

Topics

• Animals
• Antibodies, Neutralizing (pharmacology)
• Base Sequence
• CD3 Complex (immunology)
• CD4-Positive T-Lymphocytes (drug effects, virology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cell Line
• Cytokines (drug effects, immunology)
• Gene Expression Regulation, Viral (drug effects)
• HEK293 Cells
• HIV Infections (drug therapy, immunology)
• HIV-1 (drug effects, immunology)
• Humans
• Immunologic Factors (pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Macaca mulatta
• Molecular Sequence Data
• Real-Time Polymerase Chain Reaction
• Receptors, Antigen, T-Cell
• Simian Acquired Immunodeficiency Syndrome (immunology)
• env Gene Products, Human Immunodeficiency Virus (immunology)