HIV Neuropathogenesis

Cytomegalovirus infects the majority of the population globally. Congenital CMV infection acquired through primary maternal infection in pregnancy is the most common intrauterine infection with a high mortality rate due to severe long-term neurodevelopmental sequelae. The demyelination and neuroinflammation during CMV infection have been attributed to altered immune response and ROS-mediated apoptosis. PARP-1 protein is linked to apoptotic neuronal loss with subsequent neurotoxicity and CNS injury as a result of PARP hyperactivation...

Studying neurological diseases have long been hampered by the lack of physiologically relevant models to resemble the complex human brain and the associated pathologies. Three-dimensional brain organoids have emerged as cutting-edge technology providing an alternative in vitro model to study healthy neural development and function as well as pathogenesis of neurological disorders and neuropathologies induced by pathogens. Nonetheless,  the absence of immune cells in current models poses a barrier to fully recapitulate brain microenvironment during the onset of HIV-1-associated neuropathogenesis...

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...

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1 H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0...

The 2022 Conference on Retroviruses and Opportunistic Infections featured new and important findings about the neurologic complications of HIV-1, COVID-19, and other infections. Long-term analyses identified that cognitive decline over time, phenotypic aging, and stroke are associated with various comorbidities in people with HIV. Neuroimaging studies showed greater neuroinflammation, white matter damage, demyelination, and overall brain aging in people with chronic HIV infection. Childhood trauma and exposure to environmental pollutants contribute to these neuroimaging findings...

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI...

HIV-associated neurocognitive impairment (HIV-NCI) is a debilitating comorbidity that reduces quality of life in 15-40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. Monocyte-derived macrophages (MDMs) harbor HIV in the CNS even in PWH on ART. We hypothesized that morphine (MOR), a metabolite of heroin, further dysregulates functional processes in MDMs to increase neuropathogenesis. We found that, in uninfected and HIV-infected primary human MDMs, MOR activates these cells by increasing phagocytosis and up-regulating reactive oxygen species...

Dendritic cells (DCs) function as a link between innate and adaptive immune responses. Retroviruses HIV-1 and HTLV-1 modulate DCs to their advantage and utilize them to propagate infection. Coinfection of HTLV-1 and HIV-1 has implications for cancer malignancies. Both viruses initially infect DCs and propagate the infection to CD4+ T cells through cell-to-cell transmission using mechanisms including the formation of virologic synapses, viral biofilms, and conduits. These retroviruses are both neurotrophic with neurovirulence determinants...

People with HIV (PWH) continue to suffer from dysfunction of the central nervous system, as evidenced by HIV-associated neurocognitive disorder (HAND), despite antiretroviral therapy and suppressed viral loads. As PWH live longer they may also be at risk of age-related neurodegenerative diseases such Alzheimer's disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). The complement system is associated with deposition of AD-related proteins such as beta amyloid (Aβ), neuroinflammation, and neurological dysfunction in PWH...

BACKGROUND: Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1-15, 1996; An et al. in Ann Neurol 40:611-6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174-5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al...

HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation...

HIV is a major global public threat burdening society, yet the exact mechanism of HIV pathogenesis needs to be elucidated. In the era of epigenetic therapy, N-terminal acetylation (Nt-acetylation) changes induced by viral infection might play a critical role in virus-host interactions in HIV infection. The mitochondrial epigenetic mechanism, predominantly Nt acetylation, holds HIV immunopathogenesis and is vastly unexplored. The challenge is to single out the specific pathological role of NAT changes in HIV-associated neurodegeneration...

This review outlines the neuropathogenesis of HIV, from initial HIV entry into the central nervous system (CNS) to chronic infection, focusing on key advancements in the last 5 years. Discoveries regarding acute HIV infection reveal timing and mechanisms of early HIV entry and replication in the CNS, early inflammatory responses, and establishment of genetically distinct viral reservoirs in the brain. Recent studies additionally explore how chronic HIV infection is maintained in the CNS, examining how the virus remains in a latent "hidden" state in diverse cells in the brain, and how this leads to sustained pathological inflammatory responses...

INTRODUCTION: HIV infection causes a wide range of neurological complications, many of which are among the most common complications of chronic HIV infection in the era of combined antiretroviral therapy. These neurological conditions arise due to complex interactions between HIV viral proteins and neuronal and glial cells that lead to the activation of various inflammatory and neurotoxic pathways across the nervous system. AREAS COVERED: This review summarizes the current literature on the pathogenesis and clinical manifestations of neurological injuries associated with HIV in the brain, spinal cord, and peripheral nervous system...

People with HIV (PWH) on antiretroviral therapy (ART) experience elevated rates of neurological impairment, despite controlling for demographic factors and comorbidities, suggesting viral or neuroimmune etiologies for these deficits. Here, we apply multimodal and cross-compartmental single-cell analyses of paired cerebrospinal fluid (CSF) and peripheral blood in PWH and uninfected controls. We demonstrate that a subset of central memory CD4+ T cells in the CSF produced HIV-1 RNA, despite apparent systemic viral suppression, and that HIV-1-infected cells were more frequently found in the CSF than in the blood...

HIV-neurocognitive impairment (HIV-NCI) can be a debilitating condition for people with HIV (PWH), despite the success of antiretroviral therapy (ART). Substance use disorder is often a comorbidity with HIV infection. The use of methamphetamine (meth) increases systemic inflammation and CNS damage in PWH. Meth may also increase neuropathogenesis through the functional dysregulation of cells that harbor HIV. Perivascular macrophages are long-lived reservoirs for HIV in the CNS. The impaired clearance of extracellular debris and increased release of reactive oxygen species (ROS) by HIV-infected macrophages cause neurotoxicity...

The neurological complications of HIV infection, known as neuroHIV, remain prevalent even in individuals on antiretroviral therapy (ART). Although the mechanism(s) underlying neuroHIV remain undefined, current data suggest that neuroinflammation is central to the development of HIV neuropathogenesis. Neuroinflammation can be exacerbated by substance use disorders, which are highly comorbid with HIV infection and substantively worsen clinical outcomes. Despite distinct mechanisms of action, all substances of abuse increase central nervous system (CNS) dopamine, suggesting that dopamine is a common mechanism by which addictive drugs potentiate neuroHIV...

BACKGROUND: Combined antiretroviral therapy suppresses HIV replication, but 30-60% of patients suffer from HIV-1 associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in HIV CNS infection. Using proteomics, we investigated possible circulating exosomal protein links to neuropathogenesis in SIV-infected rhesus macaque (RM). METHODS: Exosomes were isolated from sera of SIV-infected (SIV-Exo) and uninfected (CTL-Exo) RM (N = 3/group) by QIAGEN exoEasy kit and characterized by the qNano-IZON system...

HIV-1 is responsible for a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). The HIV transactivator of transcription (Tat) protein plays a key role in the neuropathophysiology of HAND. The Tat protein functions by transactivation of viral genes through its interaction with the transactivation response (TAR) RNA element. Subtype-specific Tat protein signatures including C31S, R57S and Q63E present in Tat subtype C has previously been linked to a lowered neuropathophysiology compared to Tat subtype B...

The achievement of an HIV cure is dependent on the eradication or permanent silencing of HIV-latent viral reservoirs, including the understudied central nervous system (CNS) reservoir. This requires a deep understanding of the molecular mechanisms of HIV's entry into the CNS, latency establishment, persistence, and reversal. Therefore, representative CNS culture models that reflect the intercellular dynamics and pathophysiology of the human brain are urgently needed in order to study the CNS viral reservoir and HIV-induced neuropathogenesis...