Similar to HIV infection in humans, SIV infection in macaques induces progressive loss of immune cell components and function, resulting in immune deficiency in nearly all untreated infected subjects. In SIV-infected macaques, 25% of animals develop terminal AIDS within 6 months of infection. The factors responsible for the development of such rapid progression are unknown. We have previously found that defects in CD8+ T cells detectable from early infection correlate to rapid progression to simian AIDS. The transcriptional screening of molecular fingerprints on different steps along the activation/effector process of splenic CD8+ cells at termination revealed a distinction in rapid compared to regular progressors, which was characterized by a decrease in classic T cell receptor (TCR) components, and an increase in Toll-like receptor (TLR) and apoptotic pathways. A TLR pathway screening in lymphoid and myeloid cells from both the spleen and from the central nervous system of infected macaques revealed that the upregulation of TLR is not in the innate immune compartment, but rather in lymphoid cells that contain adaptive immune cells. Our findings suggest that opposing effects of TCR specific signaling and TLR engagement may drive the CD8 phenotypic failure that determines a rapid disease course in HIV infection.