Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors

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.

Cannabinoids Reduce Extracellular Vesicle Release from HIV-1 Infected Myeloid Cells and Inhibit Viral Transcription

“…When the relationship between CBD and autophagy was investigated using a biotinylated-CBD pull-down from U1 monocytes and monocyte-derived macrophages for spectrometry analysis, Reactome pathway enrichment analysis showed significant enrichment of proteins in Reactome autophagy pathways (Macrophage: R-HSA-9663891, R-HSA-1236974, R-HSA-1632852, R-HSA-9612973; Monocyte: R-HSA-9646399, R-HSA-9663891, R-HSA-9612973, R-HSA-1632852, R-HSA-9613829, Supplementary Figure S14 ). Our lab recently published a study demonstrating the reduction of latency-reversing agent (LRA)-mediated production of proinflammatory EVs released from HIV-1 infected cells by two autophagy inducers, rapamycin and INK128, exhibiting a correlation between inflammation and autophagy [ 98 ]. Furthermore, other studies showed that HIV-1-mediated autophagy deregulation was shown in neurons and dendritic cells, with increased secretory autophagosomes shown in HAND patients exhibiting encephalitis [ 99 ].…”

Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread

“…Background low levels of apoptosis could also be responsible for the presence of several cellular proteins in 2 k EVs. However, we expect that these apoptotic vesicles are not derived from dying cells [ 35 , 56 ]. These findings revealed the possibility that HTLV-1 EVs may also carry important cytokines and chemokines with the potential to further regulate the immune system of an infected host.…”

Extracellular Vesicles in HTLV-1 Communication: The Story of an Invisible Messenger

“…Similarly, we recently observed that HIV-1 in PBMCs may modulate packaging of viral proteins and inflammatory cytokines into EVs, depending on the transcriptional status of the virus. These resulting EVs were able to cause inflammation in HLM-1 indicator-indicator recipient cells, as evidenced by the release of TNF-α and viral activation [ 246 ]. These data reveal the importance to clarify blood and plasma samples from EVs and to consider EVs as a biomarker of disease severity, in particular because of the potential EV-mediate effects reported that may contribute to disease severity.…”