Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251- and simian-human immunodeficiency virus KU2-infected macaques.

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.

Lipid matrix-based subunit vaccines: a structure-function approach to oral and parenteral immunization.

Immunization is today the most effective defense mechanism against microbial infections. Although highly effective vaccines are currently available for a number of infectious diseases, vaccine formulations can still be improved in a number of important areas. The ability to induce antigen-specific humoral and cell-mediated immunity is crucial to the development of effective prophylactic and therapeutic vaccines for HIV and other pathogens. The approach of our laboratory has been to design and test simple, highly defined antigen-lipid complexes that would stimulate antibody and cell-mediated immune responses in the absence of any nonspecific immunological activators such as Freund's adjuvant, lipopolysaccharide (LPS), or alum. These studies have provided insight into the relationships between the properties of an immunogen and the induction of the desired immune responses. We have previously utilized this approach to define the minimal structures required for the induction of antibody responses. Our more recent studies have focused on defining the parameters involved in the induction of cell-mediated and mucosal immune responses. Toward this end we have developed a new type of subunit vaccine that is effective when given orally or intramuscularly, and elucidated structure-function relationships in peptide vaccines that affect induction of CD8+ cell responses.