Although combination antiretroviral therapy has led to significant virologic suppression and improvement in immune function, neurocognitive impairment remains an important clinical complication of HIV infection. In fact, some have suggested that antiretroviral treatment might enhance the risk of minor cognitive impairment through the disruption of microglial phagocytosis of ?-amyloid. Moreover, although there has been a single documented case of a HIV cure in a patient following bone marrow transplantation, no effective strategy has been developed that can leads to eradication of virus. In the research proposed, we will examine the role of autophagy in the preservation of HIV reservoirs within the central nervous system (CNS) and identify strategies to eradicate virus from these occult sites. This research will build upon our considerable preliminary data that has established autophagy as an important mechanism of HIV pathogenesis and that modulation of autophagy can inhibit HIV and preferentially kill HIV infected cells.
The Specific Aims of this proposal are:
Aim 1 : Identification of role of HIV in the modulation of autophagy in infected microglia and astrocytes;
Aim 2 : Eradication of HIV from macrophages, microglial cells and astrocytes through the induction of autophagy and killing of HIV and/or preferential killing of HIV-infected cells;
Aim 3 : In vitro optimization of HIV eradication in target cells within the CNS resulting in the least toxicity to neurons;
Aim 4 : Eradication of HIV from resting T- cells through the induction of autophagy and preferential killing of HIV-infected cells;
and Aim 5 : In vivo eradication of HIV through the induction of autophagy combined with long-acting nano-formulated antiretroviral therapy (nanoART) in a humanized NSG mouse brain model of HIV. There are many innovative aspects to this grant proposal. First, the strategy of modulating autophagy to kill HIV and HIV-infected cells is innovative and has been pioneered by my laboratory. Second, in addition to using pharmacologic agents to induce autophagy through different pathways, we will use an innovative tat-Beclin 1 peptide that effectively enters cells an leads to the killing of HIV. Third, we will translate our in vitro findings into a novel and innovaive mouse model system to test our findings in vivo and combine our approach with the use of nano-ART to improve antiretroviral delivery to cells. Fourth, we have established an outstanding team of investigators to combine their considerable knowledge of HIV, macrophages, autophagy and NeuroAIDS in order to address this challenging problem. Finally, this innovative approach provides a novel strategy to eradicate HIV from the CNS as well as the rest of the body that if successful has the potential to be applied to all HIV-infected persons.
Although combination antiretroviral therapy has led to significant virologic suppression and improvement in immune function, neurocognitive impairment remains an important clinical complication of HIV infection. In the research proposed, we will examine the role of autophagy in the preservation of HIV reservoirs within the central nervous system and identify strategies to eradicate virus from these occult sites. This research will build upon our considerable preliminary data that has established autophagy as an important mechanism of HIV pathogenesis with the goal of inducing autophagy as a mechanism to inhibit HIV and preferentially kill HIV infected cells.
|Zhang, Gang; Luk, Brian T; Hamidy, Morcel et al. (2018) Induction of a Na+/K+-ATPase-dependent form of autophagy triggers preferential cell death of human immunodeficiency virus type-1-infected macrophages. Autophagy 14:1359-1375|
|Campbell, Grant R; Bruckman, Rachel S; Chu, Yen-Lin et al. (2018) SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells. Cell Host Microbe 24:689-702.e7|
|Campbell, Grant R; Bruckman, Rachel S; Herns, Shayna D et al. (2018) Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication. J Biol Chem 293:5808-5820|
|Garg, Ankita; Trout, Rodney; Spector, Stephen A (2017) Human Immunodeficiency Virus Type-1 Myeloid Derived Suppressor Cells Inhibit Cytomegalovirus Inflammation through Interleukin-27 and B7-H4. Sci Rep 7:44485|
|Rawat, Pratima; Spector, Stephen A (2017) Development and characterization of a human microglia cell model of HIV-1 infection. J Neurovirol 23:33-46|
|Spector, Stephen A; Rappaport, Jay (2017) HIV cure strategists: ignore the central nervous system at your patients' peril. AIDS 31:167-168|
|Garg, Ankita; Rawat, Pratima; Spector, Stephen A (2015) Interleukin 23 produced by myeloid dendritic cells contributes to T-cell dysfunction in HIV type 1 infection by inducing SOCS1 expression. J Infect Dis 211:755-68|
|Campbell, Grant R; Bruckman, Rachel S; Chu, Yen-Lin et al. (2015) Autophagy induction by histone deacetylase inhibitors inhibits HIV type 1. J Biol Chem 290:5028-40|
|Campbell, Grant R; Rawat, Pratima; Bruckman, Rachel S et al. (2015) Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration. PLoS Pathog 11:e1005018|
|Garg, Ankita; Spector, Stephen A (2014) HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity. J Infect Dis 209:441-51|
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