Human anti-HIV-1 tat sFv intrabodies for gene therapy of advanced HIV-1-infection and AIDS.
The early successes of highly active anti-retroviral therapies (HAART) for the treatment of HIV-1-infection and AIDS have raised the question as to whether there is a legitimate role for gene therapy in the treatment of this chronic infectious disease. However, in many patients the profound suppression of viral replication is short lived, particularly if patients have been treated with sequential monotherapies in the past, have been infected with a highly drug resistant isolate of HIV-1, or have temporarily discontinued therapy as a "holiday" or because of drug intolerance. In addition, life-long adherence to maintenance HAART will probably be required even in responding patients with undetectable viremia because of the reservoirs of latently infected cells that can persist for years. Gene therapy through the introduction of anti-retroviral "resistance" genes into CD4(+) T cells is one approach that could give long term protection to these HIV-1 susceptible cells in vivo. We have explored this approach by developing intrabodies to the critical HIV-1 transactivator protein, Tat that is absolutely required for HIV-1 replication. This provocative treatment approach, that will be tested in a clinical gene therapy trial, sets the groundwork for determining if anti-Tat intrabody gene therapy together with HAART can provide a treatment strategy for the immune reconstitution of HIV-1-infected patients with advanced disease.