(Taken from Abstract) In patients with chronic HIV infection, abnormalities in immune function persist following HAART, as does HIV replication. There is thus a need for new therapies, which can enhance general and HIV-specific immunity. The immune modulatory drug thalidomide was recently found to costimulate T cells and result in secondary, T cell-dependent stimulation of IL-12 production by antigen-presenting cells (APC). Costimulatory APC-T cell interactions are impaired in chronic HIV disease. The hypothesis underlying this proposal is that pharmacologic T cell costimulation compensates for pathologic deficiencies in APC-T cell interactions in HIV disease, and improves immune function. To test this, patient-based studies will be performed with the following specific aims: 1. To test if thalidomide treatment enhances HIV and CMV-specific immunity in vivo. 2. To study the effect of thalidomide on the dynamics of HIV replication in vivo. 3. To characterize cellular mechanisms of antigen-specific immune modulation by thalidomide and analogs in vitro. The core of the project is an immunologically oriented clinical trial, in which 40 well-characterized HIV and CMV-infected patients on HAART and 40 demographically matched healthy, HIV-uninfected CMV seropositive controls will be randomly assigned to low-dose thalidomide or placebo treatment for 28 days. HIV and CMV-specific T cell responses will be assessed by quantitative techniques. A positive outcome will be significant stimulation by thalidomide of HIV and CMV-specific CD8 T cell responses in the HIV+ cohort. An extensive analysis of HIV replication and genetic diversification will furnish data to elucidate the relationship between the host cellular immune response and the population dynamics of viral quasispecies, and how these are affected by an immune modulatory intervention in patients on HAART. In vitro studies will furnish a deeper understanding of the immunologic mechanism of action of thalidomide. If the results support the study hypothesis, a new approach to immune-based therapy for HIV disease will be suggested, as well as a rationale for clinical applications of an oral immune adjuvant drug.
| Haslett, Patrick A J; Hanekom, Willem A; Muller, George et al. (2003) Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 187:946-55 |
| Larsson, Marie; Fonteneau, Jean-Francois; Lirvall, Margareta et al. (2002) Activation of HIV-1 specific CD4 and CD8 T cells by human dendritic cells: roles for cross-presentation and non-infectious HIV-1 virus. AIDS 16:1319-29 |
| Aandahl, Einar Martin; Moretto, Walter J; Haslett, Patrick A et al. (2002) Inhibition of antigen-specific T cell proliferation and cytokine production by protein kinase A type I. J Immunol 169:802-8 |
