Institute for Frontier Life and Medical Sciences, Kyoto University

No. 1305 Genetic engineering of a bi-functional chimeric antigen receptor (CAR) against HIV-1 using the first heptad repeat (C46) of HIV-1 envelope glycoprotein 41.

Date: March. 28, 2019 13:00~14:00
Room: Seminar Room, 1st floor, Bldg. #2 of Institute for Frontier Life and Medical Sciences, Kyoto University
Speaker: Dong Sung An, MD, PhD
UCLA AIDS Institute/School of Nursing 
Title: Genetic engineering of a bi-functional chimeric antigen receptor (CAR) against HIV-1 using the first heptad repeat (C46) of HIV-1 envelope glycoprotein 41.

Abstract

A HIV cure is possible as demonstrated by the Berlin and London patients who were treated with CCR5-Δ32/Δ32 homozygous deficient bone marrow transplantations.

We have been developing anti HIV-1 gene reagents for HIV cure by a hematopoietic stem cell based gene therapy. Here, we present our development of a bi-functional chimeric antigen receptor (CAR) against HIV-1 using the membrane anchored HIV-1 fusion inhibitor, C46. C46 is a membrane-anchored HIV fusion inhibitor, derived from the C-terminal heptad repeat of HIV gp41 modified to express on cell surface. It blocks HIV-1 fusion by binding to the N-terminal coiled-coil domain of HIV gp41 fusion intermediate and prevents the six-helix bundle formation, analogous to the FDA approved soluble peptide drug enfuvirtide (T20, fuzion). Its safety has been tested in an anti HIV-1 hematopoietic stem cell based gene therapy phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT01734850). We hypothesized that C46 fused with CD3ζ chain could serve as a HIV-1 specific CAR via binding the other heptad repeat in HIV-1 gp41 on the Env complex of an infected cell and mediate cytotoxic activity. C46-CAR anti-HIV-1 gene reagent should also protect C46-CAR gene modified CD4+ T cells.

I will present our resent results showing protection of lentiviral vector transduced C46-CAR gene modified T cells from HIV-1 infection as well as d CTL specificity for cytolysis HIV-1-infected target cells in vitro and reduced viral load in C46-CAR modified human hematopoietic stem/progenitor cell transplanted humanized BLT mice in vivo. Thus, this novel molecule was functional both for protecting transduced T cells from HIV-1 infection, and also in directing those T cells to have effector function against infected cells.   (Language: English)

 

 

Invitator Lab. of  Systems Virology
Yoshio Koyanagi (tel:075- 751-4813)