An important feature of infections with immunodeficiency viruses - human (HIV) or simian (SIV), is the host failure to mount an effective immunological defense against the virus despite the presence of very vigorous cellular and humoral immune reactions. Nevertheless, the host's immunosurveillance pathways usually curtail virus replication in the initial stages of infection, but do not eliminate virus from the body. It has been suggested that cell-mediated immunity plays a central role in these pathways. The applicants have shown that gamma/delta T-lymphocytes are: (i) the most potent killers of HIV/SIV infected cells (Vaccine Res. 1: 183-191, 1992; Clin. Exp. Immunol. 103:177-184, 1996); and (ii) become anergic in many asymptomatic HIV-infected persons and long-term nonprogressors (J. Immunol. 157:4449-4461, 1996; Moleciilar Medicine 3:60-71, 1997). To explain these seemingly contradictory observations, the applicants have proposed that gamma/delta T cells are important """"""""first-line defense players"""""""" contributing substantially to the initial control of the vital infection, but their chronic activation also helped (probably through the cytokine release) to maintain the persistent overactivation of the immune system, which in turn may result in immune dysfunctions associated with AIDS. In this application, the investigators propose to develop and test nonpeptidic vaccines that either positively or negatively influence the activity of gamma/delta T cells in their SIV model infection of rhesus monkeys. Specifically, in Specific Aim 1, they propose to test whether vaccines containing potent nonpeptide phosphoantigens for gamma/delta T cells (such as, for example, isopentenyl pyrophosphate) alone or together with irradiated Daudi cells (expressing the most effective cell-bound antigen for gamma/delta T cells) can influence the clearance of the virus in in vivo acute infections of rhesus monkeys (Macaca mulatta).
In Specific Aim 2, the applicants plan to test whether a functional deletion of 16 T cells (achieved through either in vivo vaccination with nonpeptidic phosphorylated molecules for gamma/delta T cells, such as 2,3-diphosphoglyceric acid, or by gamma/delta T cell-specific antibody-mediated depletion) will result in better prognosis and survival. The efficacy of the in vivo and the in vitro testing will be analyzed and documented. Successful outcomes may lead to selecting novel vaccination strategies and compounds for clinical testing in human AIDS.
| Evans, P S; Enders, P J; Yin, C et al. (2001) In vitro stimulation with a non-peptidic alkylphosphate expands cells expressing Vgamma2-Jgamma1.2/Vdelta2 T-cell receptors. Immunology 104:19-27 |
