Role of pyroptosis in the pathogenesis of various neurological diseases.

Pyroptosis, an inflammatory programmed cell death process, has recently garnered significant attention due to its pivotal role in various neurological diseases. This review delves into the intricate molecular signaling pathways governing pyroptosis, encompassing both caspase-1 dependent and caspase-1 independent routes, while emphasizing the critical role played by the inflammasome machinery in initiating cell death. Notably, we explore the Nucleotide-binding domain leucine-rich repeat (NLR) containing protein family, the Absent in melanoma 2-like receptor family, and the Pyrin receptor family as essential activators of pyroptosis. Additionally, we comprehensively examine the Gasdermin family, renowned for their role as executioner proteins in pyroptosis. Central to our review is the interplay between pyroptosis and various central nervous system (CNS) cell types, including astrocytes, microglia, neurons, and the blood-brain barrier (BBB). Pyroptosis emerges as a significant factor in the pathophysiology of each cell type, highlighting its far-reaching impact on neurological diseases. This review also thoroughly addresses the involvement of pyroptosis in specific neurological conditions, such as HIV infection, drug abuse-mediated pathologies, Alzheimer's disease, and Parkinson's disease. These discussions illuminate the intricate connections between pyroptosis, chronic inflammation, and cell death in the development of these disorders. We also conducted a comparative analysis, contrasting pyroptosis with other cell death mechanisms, thereby shedding light on their unique aspects. This approach helps clarify the distinct contributions of pyroptosis to neuroinflammatory processes. In conclusion, this review offers a comprehensive exploration of the role of pyroptosis in various neurological diseases, emphasizing its multifaceted molecular mechanisms within various CNS cell types. By elucidating the link between pyroptosis and chronic inflammation in the context of neurodegenerative disorders and infections, it provides valuable insights into potential therapeutic targets for mitigating these conditions.

Opioid abuse and SIV infection in non-human primates.

Human immunodeficiency virus (HIV) and drug abuse are intertwined epidemics, leading to compromised adherence to combined antiretroviral therapy (cART) and exacerbation of NeuroHIV. As opioid abuse causes increased viral replication and load, leading to a further compromised immune system in people living with HIV (PLWH), it is paramount to address this comorbidity to reduce the NeuroHIV pathogenesis. Non-human primates are well-suited models to study mechanisms involved in HIV neuropathogenesis and provide a better understanding of the underlying mechanisms involved in the comorbidity of HIV and drug abuse, leading to the development of more effective treatments for PLWH. Additionally, using broader behavioral tests in these models can mimic mild NeuroHIV and aid in studying other neurocognitive diseases without encephalitis. The simian immunodeficiency virus (SIV)-infected rhesus macaque model is instrumental in studying the effects of opioid abuse on PLWH due to its similarity to HIV infection. The review highlights the importance of using non-human primate models to study the comorbidity of opioid abuse and HIV infection. It also emphasizes the need to consider modifiable risk factors such as gut homeostasis and pulmonary pathogenesis associated with SIV infection and opioid abuse in this model. Moreover, the review suggests that these non-human primate models can also be used in developing effective treatment strategies for NeuroHIV and opioid addiction. Therefore, non-human primate models can significantly contribute to understanding the complex interplay between HIV infection, opioid abuse, and associated comorbidities.

Potential Biomarkers in Experimental Animal Models for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a complex and multifaceted disorder that has become a significant public health concern worldwide due to its contribution to mortality and morbidity. This condition encompasses a spectrum of injuries, including axonal damage, contusions, edema, and hemorrhage. Unfortunately, specific effective therapeutic interventions to improve patient outcomes following TBI are currently lacking. Various experimental animal models have been developed to mimic TBI and evaluate potential therapeutic agents to address this issue. These models are designed to recapitulate different biomarkers and mechanisms involved in TBI. However, due to the heterogeneous nature of clinical TBI, no single experimental animal model can effectively mimic all aspects of human TBI. Accurate emulation of clinical TBI mechanisms is also tricky due to ethical considerations. Therefore, the continued study of TBI mechanisms and biomarkers, of the duration and severity of brain injury, treatment strategies, and animal model optimization is necessary. This review focuses on the pathophysiology of TBI, available experimental TBI animal models, and the range of biomarkers and detection methods for TBI. Overall, this review highlights the need for further research to improve patient outcomes and reduce the global burden of TBI.

Role of Dysregulated Autophagy in HIV Tat, Cocaine, and cART Mediated NLRP3 Activation in Microglia.

Despite the ability of combination antiretroviral therapy (cART) to suppress viremia, there is persistence low levels of HIV proteins such as Transactivator of transcription (Tat) in the central nervous system (CNS), contributing to glial activation and neuroinflammation. Accumulating evidence also implicates the role of drugs of abuse in exacerbating neurological complications associated with HIV-1. The combined effects of HIV Tat, drugs of abuse, and cART can thus create a toxic milieu in the CNS. The present study investigated the combinatorial effects of HIV-Tat, cocaine, and cART on autophagy and NLRP3 inflammasome activation. We selected a combination of three commonly used cART regimens: tenofovir, emtricitabine, and dolutegravir. Our results demonstrated that exposure of mouse primary microglia (MPMs) to these agents-HIV Tat (25 ng/ml), cocaine (1 µM), and cART (1 µM each) resulted in upregulation of autophagy markers: Beclin1, LC3B-II, and SQSTM1 with impaired lysosomal functioning involving increased lysosomal pH, decreased LAMP2 and cathepsin D, ultimately leading to dysregulated autophagy. Our findings also demonstrated activation of the NLRP3 signaling in microglia exposed to these agents. We further demonstrated that gene silencing of key autophagy protein BECN1 significantly blocked NLRP3-mediated activation of microglia. Silencing of NLRP3, however, failed to block HIV Tat, cocaine, and cART-mediated dysregulation of the autophagy-lysosomal axis; these in vitro phenomena were also validated in vivo using iTat mice administered cocaine and cART. This study thus underscores the cooperative effects of HIV Tat, cocaine, and cART in exacerbating microglial activation involving dysregulated autophagy and activation of the NLRP3 inflammasome signaling.

HIV-1 Tat-mediated microglial ferroptosis involves the miR-204-ACSL4 signaling axis.

This study was focused on exploring the role of the HIV-1 Tat protein in mediating microglial ferroptosis. Exposure of mouse primary microglial cells (mPMs) to HIV-1 Tat protein resulted in induction of ferroptosis, which was characterized by increased expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4), in turn, leading to increased generation of oxidized phosphatidylethanolamine, elevated levels of lipid peroxidation, upregulated labile iron pool (LIP) and ferritin heavy chain-1 (FTH1), decreased glutathione peroxidase-4 and mitochondrial outer membrane rupture. Also, inhibition of ferroptosis by ferrostatin-1 (Fer-1) or deferoxamine (DFO) treatment suppressed ferroptosis-related changes in mPMs. Similarly, the knockdown of ACSL4 by gene silencing also inhibited ferroptosis induced by HIV-1 Tat. Furthermore, increased lipid peroxidation resulted in increased release of proinflammatory cytokines, such as TNFα, IL6, and IL1ß and microglial activation. Pretreatment of mPMs with Fer-1 or DFO further blocked HIV-1 Tat-mediated microglial activation in vitro and reduced the expression and release of proinflammatory cytokines. We identified miR-204 as an upstream modulator of ACSL4, which was downregulated in mPMs exposed to HIV-1 Tat. Transient transfection of mPMs with miR-204 mimics reduced the expression of ACSL4 while inhibiting HIV-1 Tat-mediated ferroptosis and the release of proinflammatory cytokines. These in vitro findings were further validated in HIV-1 transgenic rats as well as HIV + ve human brain samples. Overall, this study underscores a novel mechanism(s) underlying HIV-1 Tat-mediated ferroptosis and microglial activation involving miR-204-ACSL4 signaling.

Involvement of lncRNA TUG1 in HIV-1 Tat-Induced Astrocyte Senescence.

HIV-1 infection in the era of combined antiretroviral therapy has been associated with premature aging. Among the various features of HIV-1 associated neurocognitive disorders, astrocyte senescence has been surmised as a potential cause contributing to HIV-1-induced brain aging and neurocognitive impairments. Recently, lncRNAs have also been implicated to play essential roles in the onset of cellular senescence. Herein, using human primary astrocytes (HPAs), we investigated the role of lncRNA TUG1 in HIV-1 Tat-mediated onset of astrocyte senescence. We found that HPAs exposed to HIV-1 Tat resulted in significant upregulation of lncRNA TUG1 expression that was accompanied by elevated expression of p16 and p21, respectively. Additionally, HIV-1 Tat-exposed HPAs demonstrated increased expression of senescence-associated (SA) markers-SA-ß-galactosidase (SA-ß-gal) activity and SA-heterochromatin foci-cell-cycle arrest, and increased production of reactive oxygen species and proinflammatory cytokines. Intriguingly, gene silencing of lncRNA TUG1 in HPAs also reversed HIV-1 Tat-induced upregulation of p21, p16, SA-ß gal activity, cellular activation, and proinflammatory cytokines. Furthermore, increased expression of astrocytic p16 and p21, lncRNA TUG1, and proinflammatory cytokines were observed in the prefrontal cortices of HIV-1 transgenic rats, thereby suggesting the occurrence of senescence activation in vivo. Overall, our data indicate that HIV-1 Tat-induced astrocyte senescence involves the lncRNA TUG1 and could serve as a potential therapeutic target for dampening accelerated aging associated with HIV-1/HIV-1 proteins.

Role of the gut-brain axis in HIV and drug abuse-mediated neuroinflammation.

Drug abuse and related disorders are a global public health crisis affecting millions, but to date, limited treatment options are available. Abused drugs include but are not limited to opioids, cocaine, nicotine, methamphetamine, and alcohol. Drug abuse and human immunodeficiency virus-1/acquired immune deficiency syndrome (HIV-1/AIDS) are inextricably linked. Extensive research has been done to understand the effect of prolonged drug use on neuronal signaling networks and gut microbiota. Recently, there has been rising interest in exploring the interactions between the central nervous system and the gut microbiome. This review summarizes the existing research that points toward the potential role of the gut microbiome in the pathogenesis of HIV-1-linked drug abuse and subsequent neuroinflammation and neurodegenerative disorders. Preclinical data about gut dysbiosis as a consequence of drug abuse in the context of HIV-1 has been discussed in detail, along with its implications in various neurodegenerative disorders. Understanding this interplay will help elucidate the etiology and progression of drug abuse-induced neurodegenerative disorders. This will consequently be beneficial in developing possible interventions and therapeutic options for these drug abuse-related disorders.

The Epigenetic Role of miR-124 in HIV-1 Tat- and Cocaine-Mediated Microglial Activation.

HIV-1 and drug abuse have been indissolubly allied as entwined epidemics. It is well-known that drug abuse can hasten the progression of HIV-1 and its consequences, especially in the brain, causing neuroinflammation. This study reports the combined effects of HIV-1 Transactivator of Transcription (Tat) protein and cocaine on miR-124 promoter DNA methylation and its role in microglial activation and neuroinflammation. The exposure of mouse primary microglial cells to HIV-1 Tat (25 ng/mL) and/or cocaine (10 µM) resulted in the significantly decreased expression of primary (pri)-miR-124-1, pri-miR-124-2, and mature miR-124 with a concomitant upregulation in DNMT1 expression as well as global DNA methylation. Our bisulfite-converted genomic DNA sequencing also revealed significant promoter DNA methylation in the pri-miR-124-1 and pri-miR-124-2 in HIV-1 Tat- and cocaine-exposed mouse primary microglial cells. We also found the increased expression of proinflammatory cytokines such as IL1ß, IL6 and TNF in the mouse primary microglia exposed to HIV-1 Tat and cocaine correlated with microglial activation. Overall, our findings demonstrate that the exposure of mouse primary microglia to both HIV-1 Tat and cocaine could result in intensified microglial activation via the promoter DNA hypermethylation of miR-124, leading to the exacerbated release of proinflammatory cytokines, ultimately culminating in neuroinflammation.

Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection.

The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach. We probed systemic parameters and performed single-cell examination of the targets for infection in the brain, microglia and macrophages. Morphine treatment created an immunosuppressive environment, blunting initial responses to infection, which persisted during antiretroviral treatment. Antiretroviral drug concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine treatment. Interestingly, the transcriptional signature of both microglia and brain macrophages was transformed to one of a neurodegenerative phenotype. Notably, the expression of osteopontin, a pleiotropic cytokine, was significantly elevated in microglia. This was especially notable in the white matter, which is also dually affected by HIV and opioids. Increased osteopontin expression was linked to numerous HIV neuropathogenic mechanisms, including those that can maintain a viral reservoir. The opioid morphine is detrimental to SIV/HIV infection, especially in the brain.

Role of Autophagy in HIV-1 and Drug Abuse-Mediated Neuroinflammaging.

Chronic low-grade inflammation remains an essential feature of HIV-1 infection under combined antiretroviral therapy (cART) and contributes to the accelerated cognitive defects and aging in HIV-1 infected populations, indicating cART limitations in suppressing viremia. Interestingly, ~50% of the HIV-1 infected population on cART that develops cognitive defects is complicated by drug abuse, involving the activation of cells in the central nervous system (CNS) and neurotoxin release, altogether leading to neuroinflammation. Neuroinflammation is the hallmark feature of many neurodegenerative disorders, including HIV-1-associated neurocognitive disorders (HAND). Impaired autophagy has been identified as one of the underlying mechanisms of HAND in treated HIV-1-infected people that also abuse drugs. Several lines of evidence suggest that autophagy regulates CNS cells' responses and maintains cellular hemostasis. The impairment of autophagy is associated with low-grade chronic inflammation and immune senescence, a known characteristic of pathological aging. Therefore, autophagy impairment due to CNS cells, such as neurons, microglia, astrocytes, and pericytes exposure to HIV-1/HIV-1 proteins, cART, and drug abuse could have combined toxicity, resulting in increased neuroinflammation, which ultimately leads to accelerated aging, referred to as neuroinflammaging. In this review, we focus on the potential role of autophagy in the mechanism of neuroinflammaging in the context of HIV-1 and drug abuse.

Advances in the Experimental Models of HIV-Associated Neurological Disorders.

PURPOSE OF REVIEW: Involvement of the central nervous system (CNS) in HIV-1 infection is commonly associated with neurological disorders and cognitive impairment, commonly referred to as HIV-associated neurocognitive disorders (HAND). Severe and progressive neurocognitive impairment is rarely observed in the post-cART era; however, asymptomatic and mild neurocognitive disorders still exist, despite viral suppression. Additionally, comorbid conditions can also contribute to the pathogenesis of HAND. RECENT FINDINGS: In this review, we summarize the characterization of HAND, factors contributing, and the functional impairments in both preclinical and clinical models. Specifically, we also discuss recent advances in the animal models of HAND and in in vitro cultures and the potential role of drugs of abuse in this model system of HAND. Potential peripheral biomarkers associated with HAND are also discussed. Overall, this review identifies some of the recent advances in the field of HAND in cell culture studies, animal models, clinical findings, and the limitations of each model system, which can play a key role in developing novel therapeutics in the field.

HIV-1 and drug abuse comorbidity: Lessons learned from the animal models of NeuroHIV.

Various research studies that have investigated the association between HIV infection and addiction underpin the role of various drugs of abuse in impairing immunological and non-immunological pathways of the host system, ultimately leading to augmentation of HIV infection and disease progression. These studies have included both in vitro and in vivo animal models wherein investigators have assessed the effects of various drugs on several disease parameters to decipher the impact of drugs on both HIV infection and progression of HIV-associated neurocognitive disorders (HAND). However, given the inherent limitations in the existing animal models of HAND, these investigations only recapitulated specific aspects of the disease but not the complex human syndrome. Despite the inability of HIV to infect rodents over the last 30 years, multiple strategies have been employed to develop several rodent models of HAND. While none of these models can accurately mimic the overall pathophysiology of HAND, they serve the purpose of modeling some unique aspects of HAND. This review provides an overview of various animal models used in the field and a careful evaluation of methodological strengths and limitations inherent in both the model systems and study designs to understand better how the various animal models complement one another.

NLRP3 Inflammasome Blockade Reduces Cocaine-Induced Microglial Activation and Neuroinflammation.

Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1ß expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1ß and CD11b, in both the striatum and the cortical regions. Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.

HIV TAT-mediated microglial senescence: Role of SIRT3-dependent mitochondrial oxidative stress.

The advent of combined antiretroviral treatment (cART) as a treatment for HIV-1 infection has not only resulted in a dramatic decrease in the peripheral viral load but has also led to increased life expectancy of the infected individuals. Paradoxically, increased lifespan is accompanied with higher prevalence of age-related comorbidities, including HIV-associated neurocognitive disorders (HAND). Present study was aimed at exploring the role of HIV TAT protein in mediating microglial mitochondrial oxidative stress, ultimately resulting in neuroinflammation and microglial senescence. Our findings demonstrated that exposure of mouse primary microglial cells (mPMs) to HIV TAT protein resulted in a senescence-like phenotype, that was characterized by elevated expression of both p16 and p21 proteins, increased numbers of senescence-associated-ß-galactosidase positive cells, augmented cell-cycle arrest, increased release of proinflammatory cytokines and decreased telomerase activity. Additionally, exposure of mPMs to HIV TAT also resulted downregulation of SIRT3 with a concomitant increase in mitochondrial oxidative stress. Dual luciferase reporter assay identified miR-505 as a novel target of SIRT3, which was upregulated in mPMs exposed to HIV TAT. Furthermore, transient transfection of mPMs with either the SIRT3 plasmid or miRNA-505 inhibitor upregulated the expression of SIRT3 and mitochondrial antioxidant enzymes, with a concomitant decrease in microglial senescence. These in vitro findings were also validated in the prefrontal cortices and striatum of HIV transgenic rats as well as cART-treated HIV-infected individuals. In summary, this study underscores a yet undiscovered novel mechanism(s) underlying HIV TAT-mediated induction of senescence phenotype in microglia, involving the miR-505-SIRT3 axis-mediated induction of mitochondrial oxidative stress.

N-Acetylcysteine Reverses Antiretroviral-Mediated Microglial Activation by Attenuating Autophagy-Lysosomal Dysfunction.

Successful suppression of viral replication by combined antiretroviral therapy (cART) in HIV-1 infected individuals is paradoxically also accompanied by an increased prevalence of HIV-associated neurocognitive disorders (HAND) in these individuals. HAND is characterized by a state of chronic oxidative stress and inflammation. Microglia are extremely sensitive to a plethora of stimuli, including viral proteins and cART. The current study aimed to assess the effects of cART-mediated oxidative stress on the induction of inflammatory responses in microglia. In the present study, we chose a combination of three commonly used antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine, and dolutegravir. We demonstrated that exposure of microglia to the chosen cART cocktail induced generation of reactive oxygen species, subsequently leading to lysosomal dysfunction and dysregulated autophagy, ultimately resulting in the activation of microglia. Intriguingly, the potent antioxidant, N-acetylcysteine, reversed the damaging effects of cART. These in vitro findings were further corroborated in vivo wherein cART-treated HIV transgenic (Tg) rats demonstrated increased microglial activation, exaggerated lysosome impairment, and dysregulated autophagy in the prefrontal cortices compared with HIV Tg rats not exposed to cART. Similar to in vitro findings, the treatment of HIV Tg rats with N-acetylcysteine also mitigated the deleterious effects of cART. Taken together, our findings suggest that oxidative stress-mediated lysosomal dysfunction plays a critical role in the pathogenesis of HAND in drug-treated HIV-infected individuals and that antioxidant-mediated mitigation of oxidative stress could thus be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND.

Opioid-Mediated HIV-1 Immunopathogenesis.

Despite the ability of combination antiretroviral therapy to dramatically suppress viremia, the brain continues to be a reservoir of HIV-1 low-level replication. Adding further complexity to this is the comorbidity of drug abuse with HIV-1 associated neurocognitive disorders and neuroHIV. Among several abused drugs, the use of opiates is highly prevalent in HIV-1 infected individuals, both as an abused drug as well as for pain management. Opioids and their receptors have attained notable attention owing to their ability to modulate immune functions, in turn, impacting disease progression. Various cell culture, animal and human studies have implicated the role of opioids and their receptors in modulating viral replication and virus-mediated pathology both positively and negatively. Further, the combinatorial effects of HIV-1/HIV-1 proteins and morphine have demonstrated activation of inflammatory signaling in the host system. Herein, we summarized the current knowledge on the role of opioids on peripheral immunopathogenesis, viral immunopathogenesis, epigenetic profiles of the host and viral genome, neuropathogenesis of SIV/SHIV-infected non-human primates, blood-brain-barrier, HIV-1 viral latency, and viral rebound. Overall, this review provides recent insights into the role of opioids in HIV-1 immunopathogenesis. Graphical abstract.

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging.

Despite the effectiveness of combined antiretroviral therapy (cART) in suppressing virus replication, chronic inflammation remains one of the cardinal features intersecting HIV-1, cART, drug abuse, and likely contributes to the accelerated neurocognitive decline and aging in people living with HIV-1 (PLWH) that abuse drugs. It is also estimated that ~30-60% of PLWH on cART develop cognitive deficits associated with HIV-1-associated neurocognitive disorders (HAND), with symptomatology ranging from asymptomatic to mild, neurocognitive impairments. Adding further complexity to HAND is the comorbidity of drug abuse in PLWH involving activated immune responses and the release of neurotoxins, which, in turn, mediate neuroinflammation. Premature or accelerated aging is another feature of drug abusing PLWH on cART regimes. Emerging studies implicate the role of HIV-1/HIV-1 proteins, cART, and abused drugs in altering the inflammasome signaling in the central nervous system (CNS) cells. It is thus likely that exposure of these cells to HIV-1/HIV-1 proteins, cART, and/or abused drugs could have synergistic/additive effects on the activation of inflammasomes, in turn, leading to exacerbated neuroinflammation, ultimately resulting in premature aging referred to as "inflammaging" In this review, we summarize the current knowledge of inflammasome activation, neuroinflammation, and aging in central nervous system (CNS) cells such as microglia, astrocytes, and neurons in the context of HIV-1 and drug abuse.

HIV-1 Tat-mediated astrocytic amyloidosis involves the HIF-1α/lncRNA BACE1-AS axis.

Increased life expectancy of patients diagnosed with HIV in the current era of antiretroviral therapy is unfortunately accompanied with the prevalence of HIV-associated neurocognitive disorders (HANDs) and risk of comorbidities such as Alzheimer-like pathology. HIV-1 transactivator of transcription (Tat) protein has been shown to induce the production of toxic neuronal amyloid protein and also enhance neurotoxicity. The contribution of astrocytes in Tat-mediated amyloidosis remains an enigma. We report here, in simian immunodeficiency virus (SIV)+ rhesus macaques and patients diagnosed with HIV, brain region-specific up-regulation of amyloid precursor protein (APP) and Aß (40 and 42) in astrocytes. In addition, we find increased expression of ß-site cleaving enzyme (BACE1), APP, and Aß in human primary astrocytes (HPAs) exposed to Tat. Mechanisms involved up-regulation of hypoxia-inducible factor (HIF-1α), its translocation and binding to the long noncoding RNA (lncRNA) BACE1-antisense transcript (BACE1-AS), resulting, in turn, in the formation of the BACE1-AS/BACE1 RNA complex, subsequently leading to increased BACE1 protein, and activity and generation of Aß-42. Gene silencing approaches confirmed the regulatory role of HIF-1α in BACE1-AS/BACE1 in Tat-mediated amyloidosis. This is the first report implicating the role of the HIF-1α/lncRNABACE1-AS/BACE1 axis in Tat-mediated induction of astrocytic amyloidosis, which could be targeted as adjunctive therapies for HAND-associated Alzheimer-like comorbidity.