Grant: Operating Grant: Innovative Biomedical and Clinical HIV/AIDS Research

Monocytic cells play a key role in HIV disease progression. Macrophages are productively infected by HIV as are activated CD4+ T cells, however, unlike T cells, macrophages survive HIV replication without being killed and their numbers do not decline in AIDS patients. Persistently infected Macrophages with active HIV replication have been detected in patients receiving highly active anti-retroviral therapy (HAART) and represent a key challenge to eliminate HIV infection. Reservoir formation is a major impediment to finding sterile cure for HIV infections. To eradicate HIV, it is imperative to eliminate both HIV-infected CD4+ T cells and macrophages reservoirs. In the recent past, most research has focused on eliminating the latent reservoir CD4+ T cells. However, very little is known about the potential elimination of HIV-infected macrophages. To eradicate HIV, it is essential to understand the manner of HIV reservoir formation in macrophages by identifying genes responsible for cell death (apoptosis-related) and signaling proteins involved in this process. For this, we have shown for the first time a critical protective role for inhibitors of apoptosis (IAP) genes. Inhibitors specific for IAPs (Smac mimetics), are currently being evaluated for cancer therapy, and could have applications in killing HIV-infected macrophages. Our initial observations show that Smac mimetics, known to target IAP, for degradation, were able to cause death of HIV-infected macrophages without affecting uninfected macrophages. This proposal outlines the role of IAPs and Smac mimetics and the signaling pathways involved in the development of resistance to cell death of macrophages infected with HIV, specific killing of HIV-infected macrophages in vitro as well as in the in vivo experimental humanized mouse model (BLT, bone-marrow, liver and thymus). We expect that the knowledge generated will have potential to be translated into interventions aimed at eradicating HIV infection.