Autoimmunity, anergy, lentiviral immunity and disease

Abstract: Autoimmune antibodies and autoimmune responses have been characterized in both human HIV infection and the rhesus macaque (RM) non-human primate model of SIV infection and reasoned to contribute to the pathogenesis of AIDS. Many theories for the induction and maintenance of such responses have been entertained including molecular mimicry between HIV proteins and self molecules, CD4+ T cell loss accompanied by loss of normal immune regulation that dictate self–non-self-reactivity, defective negative/positive selection of T cells to name a few. The precise mechanisms that lead to such immune dysfunction is difficult to study in humans. Our lab has been studying such autoimmune responses in both SIV-infected RM and sooty mangabeys (SM), a species from Africa that are naturally infected with SIV but do not display any detectable signs of immune deficiency or autoimmunity. We submit that this model is an important model since it allows for narrowing down those mechanisms and pathways that are a result of lentiviral infection per se from those that specifically cause disease including autoimmunity. During the course of these studies, we have ruled out a role for plasma and cellular viral loads, anti-viral humoral responses and a variety of cell signaling pathways. We have identified select pathways that appear to play roles in the pathogenesis of lentiviral infection and disease. These include pathways involved in innocent bystander killing by apoptosis of CD4+ T cells, role for differential regulation of the cell cycle, and a role for distinct host proteins that get incorporated by the virions as they are assembled and either bud out of CD4+ T cells or exit the cells in the form of multi-vesicular endosomal particles from monocytes/macrophages from SIV-infected disease susceptible RM and disease-resistant SM. We present our current working model and hypotheses that are designed to elucidate differences that are responsible for such distinct outcomes of lentiviral infection, autoimmunity and disease. We believe that such findings have important implications for the design of vaccines against human HIV infection. [Copyright &y& Elsevier]