Novel strategies for characterizing T Cell responses in SIV-infected rhesus monkeys

Abstract

Human Immunodeficiency Virus (HIV) is the cause of Acquired Immune Deficiency Syndrome (AIDS) and has killed over 25 million people since the disease was first recognized in 1981. As of 2007, 33 million people globally are infected with HIV and this number is growing. HIV infects and depletes CD4+ helper T cells, affecting the ability of the immune system to defend the host against common infections. While anti-retroviral therapy has decreased morbidity and mortality, these drugs are not curative. In addition, they are beyond the financial reach of many HIV infected patients. Thus, the development of strategies to control HIV spread is a high priority. The most relevant animal model for studying HIV is the Simian Immunodeficiency Virus (SIV) - infected rhesus monkey. While HIV research has focused on studying peripheral blood specimens, mucosal sites have recently been identified as a focal point for HIV replication and tissue destruction. They are usually the sites of primary infection in the setting of sexual transmission and they are also important sites of immune depletion. If methods for controlling the replication of the virus early after infection in mucosal sites are available, it may be possible to eliminate the virus prior to systemic spread. While strategies for generating strong neutralizing antibody responses have not yet been developed, emerging data suggest that CD8+ cytotoxic T cells can contribute substantially to early virus control. It is important to study CD8+ T cells in the setting of SIV infection in rhesus monkeys, particularly in mucosal sites, using functional as well as transcriptional assays.

(cont.) One of the challenges in studying mucosal cellular immunity is the limited number of cells available in biopsies, making traditional assay systems such as flow cytometry very difficult to employ. Here, technologies for isolating rare cell populations and extracting RNA from these cells for gene expression analysis were developed. These technologies were then applied to peripheral blood specimens, looking at gene expression differences between virus-specific CD8+ T cells in Mamu-A*01+ and Mamu-A*02+ monkeys. The ultimate goal of these studies is to gain a better understanding of SIV immunopathogenesis (as a model for HIV immunopathogenesis) and to find a way to control or eliminate the virus.