T-cell engineering by a chimeric T-cell receptor with antibody-type specificity for the HIV-1 gp120

Abstract

Immune-based approaches of cell therapy against viral pathogens such as the human immunodeficiency virus type 1 (HIV-1) could be of primary importance for the control of this viral infection. Here, we designed a chimeric cell surface receptor (105TCR) to provide primary human T-lymphocytes with antibody-type specificity for the HIV-1 envelope glycoprotein. This receptor includes the single chain Fv domain of the neutralizing anti-gp120 human monoclonal antibody F105, CD8a hinge and the transmembrane and the cytoplasmic domains of TCRz. Our results show that 105TCR is expressed at the cellular surface and is capable of recognizing the HIV-1 envelope glycoprotein inducing highly efficient effector T-cell responses, including extracellular signal-regulated kinase phosphorylation and cytokine secretion. Moreover, human primary CD8+ T-lymphocytes transduced by oncoretroviral and lentiviral vectors containing the 105TCR gene are able to mediate in vitro-specific cytolysis of envelope-expressing cells and HIV-1-infected CD4+ T-lymphocytes. These findings suggest that 105TCR is particularly suited for in vivo efficacy studies. Gene Therapy (2005) 12, 299-310.

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…[7][8][9][10][11] Because residual HIV expression continues despite effective ART [12][13][14][15][16] and is required for viral rebound, HIV-infected cells should theoretically be targetable by a T cell therapeutic agent. Several mechanisms are thought to be responsible for the apparent failure of autologous cytotoxic T lymphocytes (CTLs) to clear reactivated cells in HIV-infected individuals: HIV evolution prior to ART quickly selects for CTL escape mutations; [17][18][19] HIV Nef mediates downregulation of major histocompatibility complex class I (MHC-I), 20,21 protecting HIV-infected cells from T cell receptor (TCR)-dependent CTL killing; and HIV-specific CTL responses may be limited by exhaustion 22,23 or peripheral immune tolerance.…”

Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

“…Previous reports have described the generation of HIV-1-specific CAR-T cells by connection of an extracellular antigenbinding domain to intracellular T cell activation domains (e.g., CD3 and CD28). The former can be a single-chain variable fragment (scFv) (26)(27)(28)(29)(30) or a natural molecule, such as CD4 (26,27,(31)(32)(33)(34)(35)(36), capable of directly inducing the death of cells expressing the viral envelope glycoprotein (Env). However, it remains to be determined whether these CAR-T cells can be used to kill the reactivated HIV-1 latently infected cells from the infected individuals receiving suppressive cART.…”

T Cells Engineered with a Cytomegalovirus-Specific Chimeric Immunoreceptor

“…The receptor specificity is determined by extracellular single-chain fragments of the variable region (scFv) that recognize predefined antigens and can easily be altered by selecting an appropriate scFv (16). Recombinant immunoreceptors have been successfully developed against a number of tumor antigens (16) but against only a few viral proteins from HIV and hepatitis B virus (6,20,22) and not against CMV.…”

“…The receptor specificity is determined by extracellular single-chain fragments of the variable region (scFv) that recognize predefined antigens and can easily be altered by selecting an appropriate scFv (16). Recombinant immunoreceptors have been successfully developed against a number of tumor antigens (16) but against only a few viral proteins from HIV and hepatitis B virus (6,20,22) and not against CMV.In human CMV infection, the analysis of the physiological cytotoxic T lymphocyte (CTL) response has been focused on a limited set of proteins, namely, the proteins pp65, IE1, and IE2; recent and more extensive studies have shown that glycoprotein B (gB) as well as other CMV glycoproteins is also able to evoke adaptive T cell responses (32, 34). Notably, the CMV gB is expressed at the cell surface during the early or delayed early phase of CMV replication, even in the presence of clinically used inhibitors of viral DNA replication (33).…”