SARS-CoV-2, which led to the 2020 global pandemic, is responsible for the Coronavirus Disease 2019 (COVID-19), a respiratory illness, and presents a tropism for the central nervous system. Like most members of this family, the virus is composed of structural and non-structural proteins (NSPs). The non-structural proteins are critical elements of the replication and transcription complex (RTC), as well as immune system evasion. Through hijacking the endoplasmic reticulum (ER) membrane, NSPs help the virus establish the RTC, inducing ER stress after membrane rearrangement and causing severe neuronal disturbance. In this review, we focus on the role of Nsp3, 4, and 6 in intracellular membrane rearrangement and evaluate the potential disruption of the central nervous system and the neurodegeneration which it could trigger. Studies of these NSPs will not only bring to light their specific role in viral infection but also facilitate the discovery of novel targeted drugs.

Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

Favipiravir and remdesivir, inhibitors of RNA-dependent RNA polymerase (RdRp) were recently suggested as a potential SARS-CoV2 inhibitors. Since favipiravir and remdesivir target a critical and a viral-specific process, discovering other small molecules that do the same to use as treatment could be beneficial in slowing the outbreak. Though there have been many suggested antivirals to treat SARS-CoV-2 infection, most treatments target host-associated pathways that may cause adverse effects, Small molecules inhibitors of RdRp may be the best remedy against the COVID-19 pandemic.

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Favipiravir, an inhibitor of RNA-dependent RNA polymerase used against the Japanese flu, was recently suggested as a potential COVID-19 inhibitor. Since Favipiravir targets a critical and a viral specific process, using it as a treatment could be beneficial in slowing the outbreak. Though there have been many suggested antivirals to treat SARS-CoV-2 infection, most treatments target host-associated pathways that may cause adverse effects, Favipiravir or similar combination may be the best remedy against COVID-19 pandemic.

With the introduction of combinatory antiretroviral therapy, patients infected with human immunodeficiency virus type 1 (HIV-1) can live much longer than before. However, the identification of HIV-associated neurocognitive disorder (HAND), especially HIV-associated dementia in 15-20% of patients infected with HIV-1, indicates additional complexity. These disorders turn out to be subtype dependent. Recently, many studies are ongoing trying to understand how the virus induces neuronal injury which could lead to neurological dysfunction. Most of these studies are focusing on the HIV-1 release of proteins such as Tat. However, the exact role of these proteins and their involvement in neuronal degeneration remains unidentified; this is especially true since viral proteins from different HIV-1 subtypes differ in their ability to cause neuronal damage. This review describes the role of different HIV-1 subtypes, identifies probable pathways involved in neuronal damage, the contribution of different HIV-1 subtypes to the progression of HAND, and potential treatments for HAND.

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