No abstract

No abstract

The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV-or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8 ؉ T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) ␣ and ␤ chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR ␣ and TCR ␤ chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

T he crucial role of the human immunodeficiency virus (HIV)-specific T cell and antibody response mounted by the adaptive immune system to control HIV-1 infection is well established (1). However, during acute infection, viremia is not controlled because it takes several weeks after the initiation of infection for the adaptive immune response to activate and clonally expand sufficient numbers of HIV-1-specific T cells and B cells to suppress HIV-1 infection (2). This delay in the mobilization of the adaptive immune response permits HIV-1 to rapidly replicate and disseminate during the acute phase of infection, leading to the production of high plasma viral loads, which are associated with an adverse disease course (3,4). Early control of HIV-1 replication can have a beneficial impact on the subsequent disease course, as evidenced by the ability of some individuals whose viremia was suppressed by combination antiretroviral therapy (cART) during acute infection to achieve long-term infection control despite lacking protective HLA-B alleles (5-7). Prior to the development of an effective HIV-1-specific adaptive immune response, natural killer (NK) cells, crucial innate immune effector cells which are

No abstract