Generation of antiviral, effector CD4+ T cells: A novel vaccine strategy against HIV.

摘要

The lack of pertinent virus-specific CD4+ T cell responses is a defining feature of chronic human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections and contributes to the waning of virus-specific cytotoxic T cells (CTL), eventually leading to disease progression (7, 10, 13). Another possible capacity for HIV-1-specific CD4+ T cells is the direct control of viral replication as has been described in infections by measles virus (6), human herpesvirus (16), human cytomegalovirus (CMV) (3), Epstein-Barr virus (2), lymphocytic choriomeningitis virus (LCMV) (8,11,14) and hepatitis B virus (1).; Dendritic cells (DCs) are important regulators of the immune response with the unique ability to stimulate both naive and memory T lymphocytes. In order to explore the ability of SIV-pulsed DCs to generate anti-SIV CD4+ T cell-mediated immune responses, including effector CD4+ T cells that play a direct role in suppression of viral replication, six rhesus monkeys were immunized by intradermal injection with autologous, antigen-pulsed DCs and five of the monkeys were boosted with a second dose of DCs at 3 months. Antibody responses to SIV were detected in two of the monkeys, lymphocyte-proliferative responses were detected in five of the monkeys, and cytotoxic T lymphocyte responses were detected in four of the monkeys. Macaques were orally challenged with SIVmac239 at 1–3 months after the booster inoculation. Using a novel in vitro assay of SIV replication in DCs cocultured with autologous CD4+ T cells and monocytes, suppression of viral replication was detected from five of the six monkeys at multiple time points before and after SIV challenge. Peak viral loads in the immunized monkeys were similar to those of four naïve animals but, compared with naIve monkeys, declined at 6 months to levels 1 log₁₀ or more lower in monkeys that had been vaccinated and that had ≥50% suppression of SIV replication in DCs.; To further define the nature of the SIV-specific T cell-mediated immune responses that were generated in the DC-vaccinated monkeys, we attempted to generate a primary SIV-specific T cell immune response in vitro. Since DCs undergo maturation in vivo prior to presenting antigen to T cells, various stimuli were examined for their ability to drive DC maturation both phenotypically and functionally. (Abstract shortened by UMI.)