Two comparative animal models exist for examining mechanisms of HIV pathogenesis and the factors leading to the development of AIDS, the pathogenic model of SIVmac infection in macaques and the corresponding non-pathogenic model of SIVsm infection in sooty mangabeys. Despite extensive studies with the macaque model, the mechanisms lending to immune system failure and the onset of AIDS are still not well understood, although there are some indications that genetic differences in each of these two hosts may be a key determinant in altering the course of infection. In this grant application, we propose to examine the causal relationship between genetic differences in species-specific IgG subclasses and the trapping of infectious virus particles on follicular dendritic cells. In a series of pilot studies, we will develop a novel set of reagents and assays that will be used to characterize the IgG subclasses expressed in macaque and sooty mangabey and examine the binding potential of each antibody subclass to receptors found on follicular dendritic cells.
Specific aims of the project are:1. To characterize the IgG subclasses in pig-tailed macaque (Macacca nemestrina) and sooty mangabey (Cercocebus atys). We will produce recombinant antibodies for each of the newly discovered IgG subclasses expressed in pig-tailed macaque and sooty mangabey and immunize mice with each antibody subclass to obtain anti-subclass specific monoclonal antibodies to be used for basic immunology studies.2. To characterize the IgG subclass response to SIV infection in macaque and sooty mangabey. We will examine the exact immunoglobulin profile expressed against the envelope proteins in SIV-infected macaque and sooty mangabey by developing novel western blot and quantitative ELISA assays.3. To characterize the binding of macaque and sooty mangabey IgG subclasses to Fc-gamma-receptors. We will develop quantitative assays to measure the binding kinetics of each of the macaque and mangabey IgG subclasses to two Fc-gamma-receptors, Fc-gammaRI and Fc-gammaRII. These studies will provide a detailed characterization of the IgG subclasses found in macaques and sooty mangabeys and will be the first comprehensive examination of the IgG profile produced in response to SIV infection. Concurrently, this study will offer new insight into the potential role of immunoglobulins and follicular dendritic cells in determining the disease outcome of HIV infection.
| Schindler, Michael; Munch, Jan; Kutsch, Olaf et al. (2006) Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 125:1055-67 |
