Medical Biology - Theses
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ItemManipulating cell death pathways to promote clearance of HIV-1( 2021)HIV is a chronic retroviral infection first recognised in humans 40 years ago. Untreated, it leads to progressive CD4 T cell depletion and death approximately ten years post infection. Combination anti-retroviral therapy (cART) is very effective at controlling active HIV replication. However, it needs to be continued daily for the lifetime of the infected individual, leading to a large personal and societal cost. Although the lifespan of HIV infected individuals has approached that of the general population there continues to be excess morbidity and mortality from malignancies and cardiovascular disease. A cure for HIV has eluded the scientific community so far due to a latent reservoir of the virus existing in a small minority of memory CD4 T cells, which contain HIV DNA integrated into the cellular genome. The HIV DNA integrates can be replication competent or defective. The vast majority are defective but there exists a small pool of these cells that harbour replication competent virus. These latent cells containing integrated HIV DNA downregulate their cell differentiation markers compounding the search for these cells even further. Unfortunately, these cells are unaffected by cART and during cART interruption they can reactivate and infect naive CD4 T cells. Cell death and survival in HIV infection is balanced by host and viral factors. The most well characterised form of cell death in HIV infection is apoptosis, which can occur via both extrinsic and intrinsic pathways and can be triggered by multiple events. Actively infected cells die due to viral cytopathic effects and immune clearance, but central memory CD4 T cells infected with HIV appear to be more resistant to cell death via upregulation of important anti-apoptotic proteins that block the cell death pathways. However, this upregulation can be exploited to drive cells towards death by blocking their action. SMAC mimetics are compounds that drive cell death in extrinsic apoptosis by blocking the action of IAPs. This thesis explores the addition of SMAC mimetics to standard cART therapy with the hypothesis that by targeting these upregulated proteins this can deplete the latent reservoir of HIV infection. For the first time, I show that SMAC mimetics delay the time to viral rebound in HIS HIV mice. I also describe preliminary work targeting both the extrinsic and intrinsic apoptosis pathways.