Background:  Though significant progress has been made since its discovery, we still do not know how to launch an immune response that prevents or controls HIV-1. While the cytotoxic T lymphocyte (CTL) response is a critical component of the immune response against HIV-1, it is limited by its extremely focused response to a small repertoire of HIV-1-HLA-specific epitopes, readily escapable by HIV-1 mutation. Another critical component of the immune response that contributes to control of the infection is the B cell-driven humoral response. Unfortunately, however, there is a very limited number of antibodies that neutralize the virus, and vaccines have not proved effective in inducing broadly neutralizing antibodies against HIV-1. In contrast to the reactive approach of vaccination, we present here a novel proactive approach to delineate protective CTL and antibody responses and to use this information to generate protective immunity to HIV-1.

Methods:  Using gene therapy approaches, we have generated T cells and B cells with potent anti-HIV-1 activity by reprogramming them to express highly functional HIV-1-specific T cell receptors and IgG molecules, respectively. This was accomplished by constructing lentiviral vectors encoding the TCRα and TCRβ chains cloned from potent CTL clones (CC2C and 18030.D23.18) specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. In addition, we also generated lentiviral vectors encoding HIV-1-specific heavy and light chains cloned from 2 highly neutralizing antibodies (2F5 and 2G12), again as a single transcript linked with a self-cleaving peptide.

Results:  We demonstrated that transduction with the TCR lentivector converted primary naive human CD8 lymphocytes into HIV-specific CTL with potent in vitro and in vivo HIV-1-specific activity. We also demonstrated that transduced primary B cells from HIV-1-naïve individuals produce antibodies capable of neutralizing HIV-1 infection.

Conclusions:  Using lentiviral vectors encoding HIV-1-specific TCR to transform peripheral CD8⁺ lymphocytes into HIV-1-specific CTL and encoding HIV-1 neutralizing immunoglobulin molecules to transform B cells into HIV-1-specific neutralizing antibody producers represents a novel approach to delineate structural determinants of TCR and antibody-mediated control of HIV-1, as well as a new immunotherapeutic approach to augment the HIV-1-specific immunity of patients.