Targeted delivery of cytopathicity enhancing agents, and co-ordination with shock and kill, to reduce HIV reservoirs

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Project Abstract Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, these expensive medications are not accessible for many individuals, in particular those in resource poor settings. It would therefore be of tremendous value to develop novel therapies that can drive HIV into remission, by which we mean into a state where levels of virus remain low or undetectable even when one stops taking ARV medication. At present, no such therapeutic intervention exists. Recent studies have shown that a type of molecule called BCL-2/BCL-XL antagonists is able to promote the death of HIV-infected cells, which could potentially lead to remission. A concern of these BCL-2/BCL-XL antagonists, however, is that they are associated with side-effects that are likely to be considered unacceptable. Relatedly, these molecules are not highly specific to HIV-infected cells and can also cause the death of some uninfected 'bystander' cells. We have developed a technology that allows for the selective targeting of drug-loaded gold nanoparticles to certain cell populations in vivo. In the current proposal we aim to use this technology to more selectively target BCL-2/BCL-XL antagonists to infected cell populations. In Aim 2, this targeting will be relatively broad – for example, targeting all memory CD4+ T-cells. In Aim 3, we will test approaches to specifically target delivery to only HIV infected cells. For both of these approaches 'latency reversing agents (LRAs)' may also be needed to induce some expression of HIV and promote the death of infected cells. In Aim 2, these LRAs will be provided along with BCL-2/BCL-XL antagonist be co-loading gold nanoparticles. In Aim 3, LRAs will be provided first in order to induce HIV expression, allowing subsequent specific targeting of BCL-2/BCL-XL antagonists to HIV-infected cells. Our proposal will take both of these complementary approaches from in vitro experiments through to an in vivo preclinical model. Our ultimate objective is to observe efficacy of the novel therapeutics developed by this project in these preclinical models. If observed, this would enable future clinical trials of these new therapies in people living with HIV, and potentially leading to viral remission without the need for ongoing ARV therapy.