Role of Autophagy in HIV Pathogenesis and Drug Abuse

Abstract

Autophagy is a highly regulated process in which excessive cytoplasmic materials are captured and degraded during deprivation conditions. The unique nature of autophagy that clears invasive microorganisms has made it an important cellular defense mechanism in a variety of clinical situations. In recent years, it has become increasingly clear that autophagy is extensively involved in the pathology of HIV-1. To ensure survival of the virus, HIV-1 viral proteins modulate and utilize autophagy pathway so that biosynthesis of the virus is maximized. At the same time, the abuse of illicit drugs such as methamphetamine, cocaine, morphine, and alcohol is thought to be a significant risk factor for the acquirement and progression of HIV-1. During drug-induced toxicity, autophagic activity has been proved to be altered in various cell types. Here we review the current literature on the interaction between autophagy, HIV-1, and drug abuse, and discuss the complex role of autophagy during HIV-1 pathogenesis in co-exposure to illicit drugs.

Implication of Different HIV-1 Genes in the Modulation of Autophagy

“…The influence of viral proteins on the activation of the autophagy machinery has been illustrated in numerous studies using different viruses and has shown high levels of variation due to differences in cell types and cellular environments [ 4 , 11 , 31 , 32 ]. These reports have provided important information as to the complexity of autophagy and how different steps can be targeted and functionally altered by various viral proteins.…”

“…A genomic screen has, in fact, identified a number of autophagy-related host factors, including Atg7, Atg8, Atg12, and Atg16L2, which were essential for HIV-1 infection [ 33 ]. Several excellent reviews have summarized the complex relationship between autophagy and HIV infection [ 4 , 11 , 31 , 32 ] and, in the following sections, we will discuss and update recent reports on the association between autophagy and HIV-1 with a focus on the implicated viral proteins ( Figure 2 ).…”

HIV Tat and Morphine-induced Neurodegeneration in a Beclin 1 Hemizygous Mouse Model

“…Drugs of abuse (morphine, cocaine, and methamphetamine) have been reported to compromise the immune system which when in combination with HIV, leads to an exacerbated immune depletion. Studies have reported that drug users tend to have increased risk for HIV infection, poor adherence to and efficacy of cART, and increase viral replication [79]. With respect to HAND, drug abusers show a dramatic increase in neuroinflammation, oxidative stress, alteration in BBB integrity, and frequency of HIVE [80,81].…”

“…Based on the existing literature presented in the previous chapter, HIV and opiate-induced neuropathogenesis is a relevant and significant burden. Our lab and others have shown the interactive effects of the HIV protein Tat and morphine in brain cells such as microglia and astrocytes to facilitate neuroinflammation and oxidative stress [79,106]; however, the mechanisms at play are still widely unknown. Here we propose that the autophagy pathway, which is associated with HIV replication and persistence, may be a significant contributor to the virally-induced neuroinflammation and neuronal damage observed with HIV Tat and morphine co-exposure.…”

“…Of HIV-infected patients that are IDU, a population show an accelerated progression of HIV-associated neural pathogenesis characterized by HIVE [86]. HIV viral proteins and drugs of abuse show similar mechanisms of injury such as proinflammatory response, oxidative stress, and induction of apoptosis [79]. As such, co-exposure to HIV and opiate metabolites such as morphine have been shown to enhance viral replication and exacerbate the detrimental effects of HIV/Tat in the infected brain and promote progression to AIDS dementia [102,103].…”