CD4+ T cells are dependent on antigen presenting cells (ARC) for their activation. ARC dysfunction in HIV+ individuals could accelerate or exacerbate CD4+ T cell dysfunction and may contribute to increased levels of immunodeficiency. Few studies have addressed the role of HIV infection on antigen processing and presentation. The literature has demonstrated disparate results with some studies claiming significant ARC defects and others none. This supports our overall hypothesis that APC from a subset of HIV-infected individuals have an antigen processing and presentation defect. We have developed clonal HLA class I and ll-restricted T cell hybridomas from HLA-transgenic mice that readily recognize microbial antigens presented by human APC. They will be used to measure antigen processing function in APC from HIV+ individuals. A functional costimulation assay will also be performed.
Aim 1. To determine if MN and DC from a subset of HIV+ individuals have a MHC class I, MHC class II or global defect in antigen processing and presentation. APC function in MN and DC from HIV+ patients and HIV controls will be studied with HLA-matched T hybridomas. A functional costimulation assay will be performed with naive human CD4+ T cells. In patients with defects identified, mechanisms of the dysfunction will be explored.
Aim 2. To determine if antigen processing and presentation in APC from HIV+ individuals can be enhanced by cytokines (GM-CSF, IFN-gamma, or IFN-alpha).
Aim 3. To determine if antigen processing and presentation in APC from HIV+ individuals is improved after highly active antiretroviral therapy (HAART). An understanding of antigen processing in HIV-infected individuals has significance for optimal vaccine development. Having the immunizing antigen optimally processed and presented to T cells is important for both cellular and humoral immunity. Determining specific cytokines that boost antigen processing and costimulation could augment vaccine efficacy. This work could have significant ramifications to the field of immuno-therapy for HIV. Data from the proposed studies may give a rationale for using cytokine modulators to enhance APC function thereby increasing T cell responses. Since previous studies of APC function in HIV-infected patients were complicated by their dependence on autologous T cells (i.e. HIV-induced deficits in both APC and T cells were potentially present), our studies will provide the first well-controlled comparison of APC function in HIV+ and HIV- persons.
| Canaday, David H; Chakravarti, Soma; Srivastava, Tarun et al. (2006) Class II MHC antigen presentation defect in neonatal monocytes is not correlated with decreased MHC-II expression. Cell Immunol 243:96-106 |
