Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

Abstract

HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.

Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction

“…Similarly, in chronic Staphylococcus aureus infection in mice, the survival rate was increased with SIRT2 deficiency ( 38 ), and in an SIRT2 −/− murine model, bacterial infections were reduced ( 37 ). More recently, in the context of HIV infection, the potential roles of SIRT2 in some HIV-associated comorbidities (insulin resistance and cardiovascular diseases), but also with neurocognitive disorders ( 39 ) and virus life cycle ( 40 ), have emerged. In particular, SIRT1, SIRT2, and SIRT3 can deacetylate and regulate Tat activity and, specifically for SIRT1, the interaction with Tat protein was shown to activate the HIV promoter ( 41 ).…”

NAD+ supplementation improves mAb productivity in CHO cells via a glucose metabolic shift

“…Overexpression of SIRT3 by NAD + could act as mediators of intracellular antioxidant mechanisms and protein folding and secretion capacity, which are crucial parameters for achieving high mAb production and quality. [51][52][53] In addition, it was reported that NAD + serves as an essential coenzyme and also a rate-limiting factor in the biosynthesis of various nucleotide sugars, which can impact protein glycosylation, a critical factor for recombinant protein quality. [54,55] The fact that NAD + has many functions that are desirable for recombinant protein production can make it a good candidate for a media component or supplement to improve culture performances.…”

HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND)

“…Even though antiretroviral therapy (ART) lowers the likelihood of developing HAND, the less severe forms persist [1,2] even when the viral load is undetectable [3]. To date, during the ART era, the etiology of HAND appears multifactorial yet remains incompletely elucidated [4,5]. Nevertheless, it has been established that the integrity of the blood-brain barrier is compromised in HAND [6] and that microglia, macrophages [7], and astrocytes [8] can harbor viral genetic material in the central nervous system (CNS) of HIV-controlled infected individuals.…”