This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study is focused on comparative studies of the defects in the hematologic and immunological function of the bone marrow as well as other immunological sites during pathogenic and non-pathogenic Simian Immunodeficiency Virus (SIV) infections of rhesus macaques (RMs) and sooty mangabeys (SMs), respectively. As part of this study, and to elucidate the mechanisms underlying the benign phenotype of SIV infection of SMs, we have used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs). While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV. We are hopeful that this study will provide information useful in treating the chronic aberrant immune activation of HIV-infected humans.