Intersecting roles of ER stress, mitochondrial dysfunction, autophagy, and calcium homeostasis in HIV-associated neuroco
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REVIEW
Intersecting roles of ER stress, mitochondrial dysfunction, autophagy, and calcium homeostasis in HIV-associated neurocognitive disorder Sanketh Andhavarapu 1 Tapas K. Makar 1,2
&
Akhil Katuri 1 & Joseph Bryant 1 & Vivek Patel 1 & Udit Gupta 1 & Girma Asemu 1 &
Received: 9 December 2019 / Revised: 22 April 2020 / Accepted: 19 May 2020 # Journal of NeuroVirology, Inc. 2020
Abstract HIV-associated neurocognitive disorder (HAND) is a collective term describing the spectrum of neurocognitive deficits that arise from HIV infection. Although the introduction to highly active antiretroviral therapy (HAART) has prolonged the lifespan of HIV patients, neurocognitive impairments remain prevalent, as patients are left perpetually with HIV. Currently, physicians face a challenge in treating HAND patients, so a greater understanding of the mechanisms underlying HAND pathology has been a growing focus in HIV research. Recent research has revealed the role disrupted calcium homeostasis in HIV-mediated neurotoxicity. Calcium plays a well-established role in the crosstalk between the mitochondrion and ER as well as in regulating autophagy, and ER stress, mitochondrial dysfunction, and impaired autophagic activity are considered hallmarks in several neurodegenerative and neurocognitive disorders. Therefore, it is paramount that the intricate inter-organelle signaling in relation to calcium homeostasis during HIV infection and the development of HAND is elucidated. This review consolidates current knowledge regarding the neuropathology of neurocognitive disorders and HIV infection with a focus on the underlying role of calcium during ER stress, mitochondrial dysfunction, and autophagy associated with the progression of HAND. The details of this intricate crosstalk during HAND remain relatively unknown; further research in this field can potentially aid in the development of improved therapy for patients suffering from HAND. Keywords HIV-associated neurocognitive disorder . Calcium . Endoplasmic reticulum stress . Mitochondrial dysfunction . Autophagy
HIV-associated neurocognitive disorder Human immunodeficiency virus (HIV) is an incurable virus that attacks the body’s immune system, specifically CD4+ T cells. The damaging of these specific cells can lead to unique opportunistic infections or cancers, which are signs of latestage HIV or acquired immunodeficiency syndrome (AIDS) (Bhatti et al. 2016). Antiretroviral therapy (ART) is a medicine used to treat HIV and it can potentially prolong the lives of HIV patients and prevent the transmission of HIV to others. ART has successfully increased the life expectancy of HIVinfected adults, leading to a near-normal lifespan for many
* Tapas K. Makar [email protected] 1
Institute of Human Virology, University of Maryland, 725 W Lombard St, Baltimore, MD 21201, USA
2
VA Medical Center, Baltimore, MD 21201, USA
patients (Dahabieh et al. 2015). However, because the treatment leaves many patients perpetually infected with HIV, a growing issue of comorbidities arises (Daha
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