Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells

Abstract

The use of highly active antiretroviral therapy against HIV-1 for last two decades has reduced mortality of patients through extension of nonsymptomatic phase of infection. However, HIV-1 can be preserved in longlived resting CD4+ T cells, which form a viral reservoir in infected individuals, and potentially in macrophages and astrocytes. Reactivation of viral replication is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus (shock and kill strategy). In this opinion piece, we consider potential application of therapeutic doses of irradiation, the well-known and effective stress signal that induces DNA damage and activates cellular stress response, to resolve two problems: activate HIV-1 replication and virion production in persistent reservoirs under cART and deplete infected cells through selective cell killing using DNA damage responses.

Exosomes from uninfected cells activate transcription of latent HIV-1

“…JQ1) (12,17). These methods of activating latent HIV-1 all fall under the umbrella strategy of "shock and kill," a general concept that HIV-1 can be activated from latent cells ("shocked") and killed through various mechanisms, including cART, gene therapy, use of immunotoxins, and radiation therapy (3,7,18,19). However, there have been reports where patients infected with HIV-1 and under cART have expressed low levels of HIV-1 RNA in the blood as well as low, but sustained, levels of viremia in the absence of any LRAs (20,21).…”

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…However, we can associate a combination of low to moderate dose of ionizing radiation with Latency Reversing Agents (LRAs) to eliminate these reservoirs. Thus, we might expect an increase of the rate of apoptosis/death of all the latently-infected reservoirs [100]. The modulation of apoptosis might increase the efficiency of the later approaches.…”

Follicular Dendritic Cells of Lymph Nodes as Human Immunodeficiency Virus/Simian Immunodeficiency Virus Reservoirs and Insights on Cervical Lymph Node

“…HIV cannot be eliminated from the CNS as infected monocytes or microglia have a long lifespan and low turnover ( 45 ). These monocytes and microglia within the CNS support latent HIV infection ( 46 – 49 ). Since, there is suboptimal penetration of cART ( 50 , 51 ) across the blood–brain barrier (BBB) resulting in establishment of reservoir within the CNS.…”