Neuroinflammation & pre-mature aging in the context of chronic HIV infection and drug abuse: Role of dysregulated autophagy

Abstract

In the era of combined antiretroviral therapy (cART), HIV-1 infection has transformed from adeath sentenceto a manageable, chronic disease. Although the lifeexpectancy of HIV+ individuals is comparable to that of the uninfectedsubjects paradoxically, there is increased prevalence ofage-associatedcomorbidities such asatherosclerosis, diabetes, osteoporosis & neurological deficits in the context of HIV infection. Drug abuse is a commoncomorbidityofHIV infection andis often associated withincreased neurological complications. Chronic neuroinflammation (abnormal microglial and astrocyte activation) and neuronal synaptodendritic injury are the features of CNS pathology observed inHIV (+) individualsthat are takingcART & that abuse drugs. Neuroinflammation is thedrivingforceunderlying prematureaging associated with HIV (+) infection, cART and drugs of abuse. Autophagy is a highly conserved process critical for maintaining cellular homeostasis. Dysregulated autophagyhas been shown to be linked with abnormal immune responses & aging. Recent emerging evidence implicatesthe role ofHIV/HIV proteins, cART, & abused drugsin disrupting theautophagy process in brain cells such as microglia, astrocytes, and neurons. It can thus be envisioned that co-exposure of CNS cells to HIV proteins, cART and/or abused drugs couldhavesynergistic effects on theautophagy process, thereby leading to exaggerated microglial/astrocyte activation, ultimately, promotingthe aging process. Restoration of autophagic functioncould thusprovide an alternative therapeuticstrategy formitigating neuroinflammation & ameliorating the premature aging process. The current review aims to unravel the role of dysregulated autophagy in the context of single or co-exposure of microglia, astrocytes, and neurons to HIV/HIV proteins, drugs of abuse &/or cART and will also discuss the pathways involved in dysregulated autophagy-mediated neuroinflammation.

Figure 1:

The schematic of autophagy and mitophagy

Figure 2:

7. Autophagy-mediated regulation of neuroinflammation in the context of HIV/HIV proteins, abused drugs, & cART.