Abstract
HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the “shock and kill” strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells.
Highlights
Human Immunodeficiency Virus Type-1 (HIV-1) continues to be a significant health concern, with approximately 39.5 million worldwide living with the infection [1]
We have previously demonstrated that exposure to the therapeutically-related doses of ionizing radiation (IR) induces selective cell death of HIV-1-infected T-cells through modification of tumor suppressor protein (p53) and Poly [ADP-ribose] polymerase 1 (PARP-1)
To investigate the cell-type differences in HIV-1-infected cell survival, we examined the levels of the intracellular pro-survival enzymes, catalase (CAT) and superoxide dismutase (SOD), in HIV-1-infected myeloid (U1) and T-cells (ACH2), and their uninfected parental U937 and CEM cells, respectively, in the presence and absence of IR
Summary
Human Immunodeficiency Virus Type-1 (HIV-1) continues to be a significant health concern, with approximately 39.5 million worldwide living with the infection [1]. Viruses 2020, 12, 885 chronic HIV-1 infection has been demonstrated to produce viral products in anatomical reservoirs (e.g., peripheral blood, organs, and brain) [2,3,4] These viral products, such as small non-coding RNA, genomic RNA, viral proteins, and virions in patients with chronic HIV-1 (or latent infection), may be directly associated with the development of central nervous system (CNS) impairments known as HIV-1-associated neurocognitive disorders (HAND) in 30% to 60% of infected patients [5,6,7,8,9]. A more broadly encompassing therapeutic strategy is needed to fight latency
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