Thumbnail
Access Restriction
Open

Author Kamata, Masakazu ♦ Kim, Patrick Y. ♦ Ng, Hwee L. ♦ Ringpis, Gene-Errol E. ♦ Kranz, Emiko ♦ Chan, Joshua ♦ O.'Connor, Sean ♦ Yang, Otto O. ♦ Chen, Irvin S. Y.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ AIDS VIRUS ♦ ANTIGENS ♦ CELL PROLIFERATION ♦ IMMUNOTHERAPY ♦ IN VITRO ♦ IN VIVO ♦ INSPECTION ♦ MEDICAL SURVEILLANCE ♦ MONITORING ♦ PATIENTS ♦ RECEPTORS ♦ RNA ♦ SPECIFICITY ♦ VECTORS
Abstract Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8{sup +} T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8{sup +} T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8{sup +} T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24{sup Gag} in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8{sup +} T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8{sup +} T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8{sup +} T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8{sup +} T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection suppresses its cytopathic effect.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-07-31
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 463
Issue Number 3


Open content in new tab

   Open content in new tab