A long latent phase of HIV-infection, signified by an asymptomatic state, exists between initial infection and clinically detectable, immunologic abnormalities and manifestations of the disease in HIV-infected individuals. In vitro observations suggest that stimulation of mononuclear cells with mitogens or antigens may enhance HIV expression and accelerate disease in vivo. The immune stimulation can result from exposure to simple protein antigens or from more complex immunologic stimuli induced by incidental infectious diseases. The main objective of the present proposal is to examine the role of mitogens, antigens, and incidental infections in inducing or enhancing HIV gene expression in vivo by using feline immunodeficiency virus (FIV)-infected cats as a small animal model for human AIDS. Molecular and immunohistochemical methods will be applied to localize and quantitate viral gene expression (DNA, RNA, protein) at tissue and individual cell level in vivo. Development of the disease will be followed clinically and pathologically. Regional and systemic effect of immune activation due to mitogens and antigens on FIV gene expression and disease progression will be determined. T-cell specific (concavalinA), T- and B-cell specific (poke weed mitogen) and B-cell specific (Nocardia-delipidated cell mitogen) mitogens will be used to investigate how T- and B-cell activation in vivo will influence FIV expression. For antigenic stimulus, we will use two forms of a synthetic polypeptide antigen, multi-copoly(Phe-Glu)-poly(Pro)-poly(Lys), one containing D-amino acids and the other, containing L-amino acids. The D- form induces thymus independent antibody response, whereas, L-form induces T-dependent response. If mitogenic or antigenic stimuli do upregulate FIV expression, an attempt will be made to block immune activation by systemic cyclosporinA treatment and examine FIV gene expression. To determine the effect of other microbial infections on FIV gene expression, FIV-infected cats will be exposed to three heterologous viruses: (i) a nonpathogenic retrovirus, FeSFV, (ii) an immunopathic retrovirus, FeLV, and (iii) a DNA virus, FHV1. To study the effect of a bacterial infection as an immune stimulant, living bacillus Calmette-Guerin (BCG) vaccine will be used. Results from this investigation will determine whether immune activation and heterologous infections activate FIV gene expression in vivo and if FIV-infected cats can be used as an appropriate small animal model to study mechanisms of in vivo immunopathogenesis in AIDS.
