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Zhou Z, Gong W, Hu H, Wang F, Li H, Xu F, Li H, Wang W. Functional and Structural Network Alterations in HIV-Associated Asymptomatic Neurocognitive Disorders: Evidence for Functional Disruptions Preceding Structural Changes. Neuropsychiatr Dis Treat 2025; 21:689-709. [PMID: 40190547 PMCID: PMC11971962 DOI: 10.2147/ndt.s508747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/25/2025] [Indexed: 04/09/2025] Open
Abstract
Purpose This study focuses on the asymptomatic neurocognitive impairment (ANI) stage of HIV-associated neurocognitive disorders (HAND). Using multimodal MRI and large-scale brain network analysis, we aimed to investigate alterations in functional networks, structural networks, and functional-structural coupling in persons with ANI. Patients and Methods A total of 95 participants, including 48 healthy controls and 47 persons with HIV-ANI, were enrolled. Resting-state fMRI and diffusion tensor imaging were used to construct functional and structural connectivity matrices. Graph-theoretical analysis was employed to assess inter-group differences in global metrics, nodal characteristics, and functional-structural coupling patterns. Furthermore, machine learning classifiers were used to construct and evaluate classification models based on imaging features from both groups. The performance of different models was compared to identify the optimal diagnostic model for detecting HIV-ANI. Results Structural network analysis showed no significant changes in the global or local topological properties of persons with ANI. In contrast, functional networks exhibited significant reorganization in key regions, including the visual, executive control, and default mode networks. Functional-structural coupling was significantly enhanced in the occipital and frontal networks. These changes correlated with immune status, infection duration, and cognitive performance. Furthermore, the classification model integrating graph-theoretical topological features and functional connectivity achieved the best performance, with an area under the curve (AUC) of 0.962 in the test set. Conclusion Functional network reorganization and enhanced functional-structural coupling may reflect early synaptic and dendritic damage in persons with ANI, serving as potential early warning signals for HAND progression. These findings provide sensitive biomarkers and valuable perspectives for early diagnosis and intervention.
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Affiliation(s)
- Zhongkai Zhou
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Wenru Gong
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Hong Hu
- Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China
| | - Fuchun Wang
- Center of Infectious Disease, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Hui Li
- Department of Neurology, XuanWu Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Fan Xu
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Hongjun Li
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Wei Wang
- Department of Radiology, Beijing YouAn Hospital, Capital Medical University, Beijing, People’s Republic of China
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Britton MK, DeFelice J, Porges EC, Cohen R, Li Y, Wang Y, Ibañez GE, Somboonwit C, Cook RL. Association between cannabis use disorder and greater apathy in adults with HIV. Drug Alcohol Depend 2024; 261:111354. [PMID: 38870567 PMCID: PMC11549954 DOI: 10.1016/j.drugalcdep.2024.111354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/24/2024] [Accepted: 05/30/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Apathy is prevalent among people with HIV (PWH) and is associated with poor clinical outcomes. Cannabis use and Cannabis Use Disorder (CUD) are also disproportionately prevalent among PWH. CUD and younger onset of cannabis use may be linked to apathy in the general population; however, patterns of use most strongly associated with apathy have not been firmly established, and it is unclear whether cannabis use is linked to apathy in PWH. METHODS We examined associations in 311 adult PWH between Apathy Evaluation Scale-Self (AES-S) scores and CUD history (current/past/no CUD/no cannabis use) and between AES-S scores and age of CUD onset (adolescent-onset/adult-onset). We also examined robustness of associations to adjustment for depressive symptoms (which may overlap with apathy symptoms) and alcohol use. RESULTS Current CUD was associated with greater AES-S scores relative to cannabis users with no CUD history (β = 2.13, 95 % CI = 0.37-3.90, p = 0.018). Adolescent-onset CUD was not associated with greater apathy relative to adult-onset CUD (β = 0.56, 95 % CI = -2.57 - 3.68, p = 0.7). Associations became nonsignificant after adjustment for depressive symptoms, but not after adjustment for alcohol use. Alcohol use was correlated with apathy (r = 0.19, 95 % CI: 0.076-0.29, p = 0.001). CONCLUSIONS Cannabis Use Disorder and at-risk alcohol use are associated with apathy among PWH; this finding highlights the need for substance use disorder prevention and treatment among PWH.
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Affiliation(s)
- Mark K Britton
- Center for Cognitive Aging and Memory, University of Florida, 1249 Center Drive, Gainesville, FL 32603, United States; Department of Epidemiology, University of Florida, 2004 Mowry Road, Gainesville, FL 32603, United States.
| | - Jason DeFelice
- Center for Cognitive Aging and Memory, University of Florida, 1249 Center Drive, Gainesville, FL 32603, United States
| | - Eric C Porges
- Center for Cognitive Aging and Memory, University of Florida, 1249 Center Drive, Gainesville, FL 32603, United States
| | - Ronald Cohen
- Center for Cognitive Aging and Memory, University of Florida, 1249 Center Drive, Gainesville, FL 32603, United States
| | - Yancheng Li
- Department of Epidemiology, University of Florida, 2004 Mowry Road, Gainesville, FL 32603, United States
| | - Yan Wang
- Department of Epidemiology, University of Florida, 2004 Mowry Road, Gainesville, FL 32603, United States
| | - Gladys E Ibañez
- Department of Epidemiology, Florida International University, 11200 SW 8th Street, Miami, FL 33199, United States
| | - Charurut Somboonwit
- Department of Internal Medicine, University of South Florida, 13330 USF Laurel Drive, Tampa, FL 33612, United States
| | - Robert L Cook
- Department of Epidemiology, University of Florida, 2004 Mowry Road, Gainesville, FL 32603, United States
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Xie Q, Namba MD, Buck LA, Park K, Jackson JG, Barker JM. Effects of Antiretroviral Treatment on Central and Peripheral Immune Response in Mice with EcoHIV Infection. Cells 2024; 13:882. [PMID: 38786105 PMCID: PMC11120433 DOI: 10.3390/cells13100882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.
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Affiliation(s)
- Qiaowei Xie
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Q.X.); (M.D.N.); (L.A.B.); (J.G.J.)
- Graduate Program in Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Mark D. Namba
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Q.X.); (M.D.N.); (L.A.B.); (J.G.J.)
| | - Lauren A. Buck
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Q.X.); (M.D.N.); (L.A.B.); (J.G.J.)
| | - Kyewon Park
- Center for AIDS Research, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Joshua G. Jackson
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Q.X.); (M.D.N.); (L.A.B.); (J.G.J.)
| | - Jacqueline M. Barker
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; (Q.X.); (M.D.N.); (L.A.B.); (J.G.J.)
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Xie Q, Namba MD, Buck LA, Park K, Jackson JG, Barker JM. Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.11.589109. [PMID: 38645059 PMCID: PMC11030421 DOI: 10.1101/2024.04.11.589109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
HIV infection is an ongoing global health issue despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F) and tenofovir alafenamide (TAF) on expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.
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Ross EJ, Williams RS, Viamonte M, Reynolds JM, Duncan DT, Paul RH, Carrico AW. Overamped: Stimulant Use and HIV Pathogenesis. Curr HIV/AIDS Rep 2023; 20:321-332. [PMID: 37971597 DOI: 10.1007/s11904-023-00672-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE OF REVIEW In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and crack cocaine) display elevated HIV viral load and greater immune dysregulation. RECENT FINDINGS Although rates of viral suppression have improved in the TasP era, stimulant use was independently associated with elevated viral load in 23 of 28 studies included in our review. In the 12 studies examining other HIV disease markers, there was preliminary evidence for stimulant-associated alterations in gut-immune dysfunction and cellular immunity despite effective HIV treatment. Studies generally focused on documenting the direct associations of stimulant use with biomarkers of HIV pathogenesis without placing these in the context of social determinants of health. Stimulant use is a key barrier to optimizing the effectiveness of TasP. Elucidating the microbiome-gut-brain axis pathways whereby stimulants alter neuroimmune functioning could identify viable targets for pharmacotherapies for stimulant use disorders. Examining interpersonal, neighborhood, and structural determinants that could modify the associations of stimulant use with biomarkers of HIV pathogenesis is critical to guiding the development of comprehensive, multi-level interventions.
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Affiliation(s)
- Emily J Ross
- University of Miami Miller School of Medicine, Miami, FL, USA
| | - Renessa S Williams
- University of Miami School of Nursing and Health Sciences, Coral Gables, FL, USA
| | | | - John M Reynolds
- Calder Memorial Library, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Dustin T Duncan
- Columbia University Mailman School of Public Health, New York City, NY, USA
| | - Robert H Paul
- Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO, USA
| | - Adam W Carrico
- Robert Stempel College of Public Health and Social Work, Florida International University, 11200 S.W. 8th Street, AHC5, #407, Miami, FL, 33199, USA.
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Vines L, Sotelo D, Giddens N, Manza P, Volkow ND, Wang GJ. Neurological, Behavioral, and Pathophysiological Characterization of the Co-Occurrence of Substance Use and HIV: A Narrative Review. Brain Sci 2023; 13:1480. [PMID: 37891847 PMCID: PMC10605099 DOI: 10.3390/brainsci13101480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/10/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Combined antiretroviral therapy (cART) has greatly reduced the severity of HIV-associated neurocognitive disorders in people living with HIV (PLWH); however, PLWH are more likely than the general population to use drugs and suffer from substance use disorders (SUDs) and to exhibit risky behaviors that promote HIV transmission and other infections. Dopamine-boosting psychostimulants such as cocaine and methamphetamine are some of the most widely used substances among PLWH. Chronic use of these substances disrupts brain function, structure, and cognition. PLWH with SUD have poor health outcomes driven by complex interactions between biological, neurocognitive, and social factors. Here we review the effects of comorbid HIV and psychostimulant use disorders by discussing the distinct and common effects of HIV and chronic cocaine and methamphetamine use on behavioral and neurological impairments using evidence from rodent models of HIV-associated neurocognitive impairments (Tat or gp120 protein expression) and clinical studies. We also provide a biopsychosocial perspective by discussing behavioral impairment in differentially impacted social groups and proposing interventions at both patient and population levels.
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Affiliation(s)
- Leah Vines
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.V.); (D.S.); (P.M.); (N.D.V.)
| | - Diana Sotelo
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.V.); (D.S.); (P.M.); (N.D.V.)
| | - Natasha Giddens
- Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53719, USA;
| | - Peter Manza
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.V.); (D.S.); (P.M.); (N.D.V.)
| | - Nora D. Volkow
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.V.); (D.S.); (P.M.); (N.D.V.)
| | - Gene-Jack Wang
- Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA; (L.V.); (D.S.); (P.M.); (N.D.V.)
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Namba MD, Xie Q, Barker JM. Advancing the preclinical study of comorbid neuroHIV and substance use disorders: Current perspectives and future directions. Brain Behav Immun 2023; 113:453-475. [PMID: 37567486 PMCID: PMC10528352 DOI: 10.1016/j.bbi.2023.07.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/23/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Human immunodeficiency virus (HIV) remains a persistent public health concern throughout the world. Substance use disorders (SUDs) are a common comorbidity that can worsen treatment outcomes for people living with HIV. The relationship between HIV infection and SUD outcomes is likely bidirectional, making clear interrogation of neurobehavioral outcomes challenging in clinical populations. Importantly, the mechanisms through which HIV and addictive drugs disrupt homeostatic immune and CNS function appear to be highly overlapping and synergistic within HIV-susceptible reward and motivation circuitry in the central nervous system. Decades of animal research have revealed invaluable insights into mechanisms underlying the pathophysiology SUDs and HIV, although translational studies examining comorbid SUDs and HIV are very limited due to the technical challenges of modeling HIV infection preclinically. In this review, we discuss preclinical animal models of HIV and highlight key pathophysiological characteristics of each model, with a particular emphasis on rodent models of HIV. We then review the implementation of these models in preclinical SUD research and identify key gaps in knowledge in the field. Finally, we discuss how cutting-edge behavioral neuroscience tools, which have revealed key insights into the neurobehavioral mechanisms of SUDs, can be applied to preclinical animal models of HIV to reveal potential, novel treatment avenues for comorbid HIV and SUDs. Here, we argue that future preclinical SUD research would benefit from incorporating comorbidities such as HIV into animal models and would facilitate the discovery of more refined, subpopulation-specific mechanisms and effective SUD prevention and treatment targets.
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Affiliation(s)
- Mark D Namba
- Department of Pharmacology & Physiology, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Qiaowei Xie
- Department of Pharmacology & Physiology, College of Medicine, Drexel University, Philadelphia, PA, USA
| | - Jacqueline M Barker
- Department of Pharmacology & Physiology, College of Medicine, Drexel University, Philadelphia, PA, USA.
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Singh S, Thangaraj A, Chivero ET, Guo ML, Periyasamy P, Buch S. Role of Dysregulated Autophagy in HIV Tat, Cocaine, and cART Mediated NLRP3 Activation in Microglia. J Neuroimmune Pharmacol 2023; 18:327-347. [PMID: 37148425 PMCID: PMC10729649 DOI: 10.1007/s11481-023-10063-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 04/05/2023] [Indexed: 05/08/2023]
Abstract
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.
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Affiliation(s)
- Seema Singh
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Annadurai Thangaraj
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
- Centre for Excellence in Nanobio Translational Research, Department of Pharmaceutical Technology, Anna University, BIT Campus, Tiruchirappalli, Tamil Nadu, India
| | - Ernest T Chivero
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
- Department of Psychology, University of Nebraska Omaha, Omaha, NE, 68182-0001, USA
| | - Ming-Lei Guo
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
- Department of Pathology and Anatomy, Eastern Virginia Medical School, Norfolk, VA, 23507, USA.
| | - Palsamy Periyasamy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
| | - Shilpa Buch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
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Pla-Tenorio J, Roig AM, García-Cesaní PA, Santiago LA, Sepulveda-Orengo MT, Noel RJ. Astrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 5:100108. [PMID: 38020814 PMCID: PMC10663134 DOI: 10.1016/j.crneur.2023.100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 06/05/2023] [Accepted: 08/18/2023] [Indexed: 12/01/2023] Open
Abstract
The roles of astrocytes as reservoirs and producers of a subset of viral proteins in the HIV infected brain have been studied extensively as a key to understanding HIV-associated neurocognitive disorders (HAND). However, their comprehensive role in the context of intersecting substance use and neurocircuitry of the reward pathway and HAND has yet to be fully explained. Use of methamphetamines, cocaine, or opioids in the context of HIV infection have been shown to lead to a faster progression of HAND. Glutamatergic, dopaminergic, and GABAergic systems are implicated in the development of HAND-induced cognitive impairments. A thorough review of scientific literature exploring the variety of mechanisms in which these drugs exert their effects on the HIV brain and astrocytes has revealed marked areas of convergence in overexcitation leading to increased drug-seeking behavior, inflammation, apoptosis, and irreversible neurotoxicity. The present review investigates astrocytes, the neural pathways, and mechanisms of drug disruption that ultimately play a larger holistic role in terms of HIV progression and drug use. There are opportunities for future research, therapeutic intervention, and preventive strategies to diminish HAND in the subset population of patients with HIV and substance use disorder.
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Affiliation(s)
- Jessalyn Pla-Tenorio
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Angela M. Roig
- Seattle Children's Hospital, MS OC.7.830, 4800 Sand Point Way NE, Seattle, WA, 98105-0371, United States
| | - Paulina A. García-Cesaní
- Bella Vista Hospital, Family Medicine Residency, Carr. 349 Km 2.7, Cerro Las Mesas, Mayaguez, PR, 00681, Puerto Rico
| | - Luis A. Santiago
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Marian T. Sepulveda-Orengo
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Richard J. Noel
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
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Liu N, Zhao S, Li Y, Li M, Guo Y, Luo X. Gold nanoparticles-decorated peptide hydrogel for antifouling electrochemical dopamine determination. Mikrochim Acta 2023; 190:199. [PMID: 37140766 DOI: 10.1007/s00604-023-05785-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/12/2023] [Indexed: 05/05/2023]
Abstract
A reliable and brief ultralow fouling electrochemical sensing system capable of monitoring targets in complex biological media was constructed and validated based on gold nanoparticles-peptide hydrogel-modified screen-printed electrode. The self-assembled zwitterionic peptide hydrogel was prepared by a newly designed peptide sequence of Phe-Phe-Cys-Cys-(Glu-Lys)3 with the N-terminal modified with a fluorene methoxycarbonyl group. The thiol groups on cysteine of the designed peptide are able to self-assemble with AuNPs to form a three-dimensional nanonetwork structure, which showed satisfactory antifouling capability in complex biological media (human serum). The developed gold nanoparticles-peptide hydrogel-based electrochemical sensing platform displayed notably sensing properties for dopamine determination, with a wide linear range (from 0.2 nM to 1.9 μM), a low limit of detection (0.12 nM), and an excellent selectivity. This highly sensitive and ultralow fouling electrochemical sensor was fabricated via simple preparation with concise components that avoid the accumulation of layers with single functional material and complex activation processes. This ultralow fouling and highly sensitive strategy based on the gold nanoparticles-peptide hydrogel with a three-dimensional nanonetwork offers a solution to the current situation of various low-fouling sensing systems facing impaired sensitivity and provides a potential path for the practical application of electrochemical sensors.
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Affiliation(s)
- Nianzu Liu
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China
- Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Shuju Zhao
- Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Yanxin Li
- Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Mingxuan Li
- Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China
| | - Yingshu Guo
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China
| | - Xiliang Luo
- Key Laboratory of Optic-Electric Sensing and Analytical Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao, 266042, China.
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11
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Madhuravasal Krishnan J, Kong L, Karns R, Medvedovic M, Sherman KE, Blackard JT. The Synthetic Opioid Fentanyl Increases HIV Replication and Chemokine Co-Receptor Expression in Lymphocyte Cell Lines. Viruses 2023; 15:1027. [PMID: 37113007 PMCID: PMC10145664 DOI: 10.3390/v15041027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/11/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND In the United States, the illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis. Synthetic opioids are known to enhance viral replication and to suppress immunologic responses, but their effects on HIV pathogenesis remain unclear. Thus, we examined the impact of fentanyl on HIV-susceptible and HIV-infected cell types. METHODS TZM-bl and HIV-infected lymphocyte cells were incubated with fentanyl at varying concentrations. Expression levels of the CXCR4 and CCR5 chemokine receptors and HIV p24 antigen were quantified with ELISA. HIV proviral DNA was quantified using SYBR RT-PCR. Cell viability was detected with the MTT assay. RNAseq was performed to characterize cellular gene regulation in the presence of fentanyl. RESULTS Fentanyl enhanced expression of both chemokine receptor levels in a dose-dependent manner in HIV-susceptible and infected cell lines. Similarly, fentanyl induced viral expression in HIV-exposed TZM-bl cells and in HIV-infected lymphocyte cell lines. Multiple genes associated with apoptosis, antiviral/interferon response, chemokine signaling, and NFκB signaling were differentially regulated. CONCLUSIONS Synthetic opioid fentanyl impacts HIV replication and chemokine co-receptor expression. Increased virus levels suggest that opioid use may increase the likelihood of transmission and accelerate disease progression.
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Affiliation(s)
- Janani Madhuravasal Krishnan
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
| | - Ling Kong
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
| | - Rebekah Karns
- Digestive Health Center, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA
| | - Mario Medvedovic
- Department of Environmental & Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Kenneth E. Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jason T. Blackard
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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12
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Du X, Zhang Q, Hao J, Gong X, Liu J, Chen J. Global trends in depression among patients living with HIV: A bibliometric analysis. Front Psychol 2023; 14:1125300. [PMID: 36968702 PMCID: PMC10036061 DOI: 10.3389/fpsyg.2023.1125300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/13/2023] [Indexed: 03/12/2023] Open
Abstract
BackgroundHuman immunodeficiency virus (HIV) related depression has seriously affected the quality of life and treatment outcomes of patients living with HIV (PLWH), which has become a hot topic in recent years. This study aims to discover the main keywords, predict frontier topics, and give meaningful suggestions for researchers by bibliometric analysis.MethodsPublications between 1999 and 2022 on depression in HIV/AIDS were searched in the Web of Science core collection. Microsoft Excel 2010 and VOSviewer were utilized to key contributors (e.g., authors, journals, institutions, and countries). VOSviewer and CiteSpace were used to analyze the knowledge evolution, collaborative maps, hot topics, and keywords trends in this field.ResultsIn total, 8,190 publications were included in the final analysis. From 1999 to 2021, the number of published articles roughly presents a steadily increasing trend. The United States, South Africa, and the United Kingdom were three key contributing countries/regions to this field. University Calif San Francisco (United States), University Calif Los Angeles (United States), and Johns Hopkins University (United States) were three key contributing institutions. Safren, Steven A. was the most productive and highest cited author. AIDS Care was the top prolific journal. Antiretroviral therapy and adherence, men has sex with men, mental health, substance abuse, stigma, and Sub-Saharan Africa were the central topics regarding the depression-related research in HIV/AIDS.ConclusionThis bibliometric analysis reported the publication trend, major contributing countries/regions, institutions, authors, journals and mapped the knowledge network of depression-related research on HIV/AIDS. In this field, topics such as “adherence,” “mental health,” “substance abuse,” “stigma,” “men who have sex with men” and “South Africa” have attracted considerable attention.
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Affiliation(s)
- Xiaoyu Du
- Xiangya Nursing School, Central South University, Changsha, China
| | - Qian Zhang
- Xiangya Hospital Department of Neurosurgery, Central South University, Changsha, China
| | - Jiaqi Hao
- Xiangya Nursing School, Central South University, Changsha, China
| | - Xilong Gong
- Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jing Liu
- Xiangya Nursing School, Central South University, Changsha, China
- *Correspondence: Jing Liu,
| | - Jia Chen
- Xiangya Nursing School, Central South University, Changsha, China
- Jia Chen,
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13
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McLaurin KA, Li H, Mactutus CF, Harrod SB, Booze RM. Disrupted Decision-Making: EcoHIV Inoculation in Cocaine Dependent Rats. Int J Mol Sci 2022; 23:9100. [PMID: 36012364 PMCID: PMC9409394 DOI: 10.3390/ijms23169100] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 02/05/2023] Open
Abstract
Independently, chronic cocaine use and HIV-1 viral protein exposure induce neuroadaptations in the frontal-striatal circuit as evidenced by both clinical and preclinical studies; how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use, however, has remained elusive. After establishing experience with both sucrose and cocaine self-administration, a pretest-posttest experimental design was utilized to evaluate preference judgment, a simple form of decision-making dependent upon the integrity of frontal-striatal circuit function. During the pretest assessment, male rats exhibited a clear preference for cocaine, whereas female animals preferred sucrose. Two posttest evaluations (3 days and 6 weeks post inoculation) revealed that, independent of biological sex, inoculation with chimeric HIV (EcoHIV), but not saline, disrupted decision-making. Prominent structural alterations in the frontal-striatal circuit were evidenced by synaptodendritic alterations in pyramidal neurons in the medial prefrontal cortex. Thus, the EcoHIV rat affords a valid animal model to critically investigate how the frontal-striatal circuit responds to HIV-1 infection following chronic drug use.
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Affiliation(s)
| | | | | | | | - Rosemarie M. Booze
- Cognitive and Neural Science Program, Department of Psychology, University of South Carolina, Columbia, SC 29208, USA
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14
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Bischoff-Grethe A, Ellis RJ, Tapert SF, Paulus MP, Grant I. Prior Methamphetamine Use Disorder History Does Not Impair Interoceptive Processing of Soft Touch in HIV Infection. Viruses 2021; 13:v13122476. [PMID: 34960745 PMCID: PMC8705776 DOI: 10.3390/v13122476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/05/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: Interoception, defined as the sense of the internal state of one’s body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. Methods: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. Results: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. Conclusions: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.
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Affiliation(s)
- Amanda Bischoff-Grethe
- Department of Psychiatry, University of California, San Diego 9500 Gilman Drive, MC 0738 La Jolla, San Diego, CA 92093, USA; (S.F.T.); (I.G.)
- Correspondence:
| | - Ronald J. Ellis
- Department of Neurosciences, University of California, La Jolla, San Diego, CA 92093, USA;
| | - Susan F. Tapert
- Department of Psychiatry, University of California, San Diego 9500 Gilman Drive, MC 0738 La Jolla, San Diego, CA 92093, USA; (S.F.T.); (I.G.)
| | | | - Igor Grant
- Department of Psychiatry, University of California, San Diego 9500 Gilman Drive, MC 0738 La Jolla, San Diego, CA 92093, USA; (S.F.T.); (I.G.)
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15
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League AF, Gorman BL, Hermes DJ, Johnson CT, Jacobs IR, Yadav-Samudrala BJ, Poklis JL, Niphakis MJ, Cravatt BF, Lichtman AH, Ignatowska-Jankowska BM, Fitting S. Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat. Front Neurol 2021; 12:651272. [PMID: 34484091 PMCID: PMC8415271 DOI: 10.3389/fneur.2021.651272] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/12/2021] [Indexed: 12/01/2022] Open
Abstract
While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(–) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(–) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection.
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Affiliation(s)
- Alexis F League
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Benjamin L Gorman
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Douglas J Hermes
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Clare T Johnson
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Ian R Jacobs
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Barkha J Yadav-Samudrala
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
| | - Justin L Poklis
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Micah J Niphakis
- Department of Chemistry, Scripps Research Institute, La Jolla, CA, United States
| | - Benjamin F Cravatt
- Department of Chemistry, Scripps Research Institute, La Jolla, CA, United States
| | - Aron H Lichtman
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | | | - Sylvia Fitting
- Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
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16
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McLaurin KA, Harris M, Madormo V, Harrod SB, Mactutus CF, Booze RM. HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits. Cells 2021; 10:2158. [PMID: 34440928 PMCID: PMC8392364 DOI: 10.3390/cells10082158] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 12/12/2022] Open
Abstract
Individuals living with human immunodeficiency virus type 1 (HIV-1) are often plagued by debilitating neurocognitive impairments and affective alterations;the pathophysiology underlying these deficits likely includes dopaminergic system dysfunction. The present review utilized four interrelated aims to critically examine the evidence for dopaminergic alterations following HIV-1 viral protein exposure. First, basal dopamine (DA) values are dependent upon both brain region andexperimental approach (i.e., high-performance liquid chromatography, microdialysis or fast-scan cyclic voltammetry). Second, neurochemical measurements overwhelmingly support decreased DA concentrations following chronic HIV-1 viral protein exposure. Neurocognitive impairments, including alterations in pre-attentive processes and attention, as well as apathetic behaviors, provide an additional line of evidence for dopaminergic deficits in HIV-1. Third, to date, there is no compelling evidence that combination antiretroviral therapy (cART), the primary treatment regimen for HIV-1 seropositive individuals, has any direct pharmacological action on the dopaminergic system. Fourth, the infection of microglia by HIV-1 viral proteins may mechanistically underlie the dopamine deficit observed following chronic HIV-1 viral protein exposure. An inclusive and critical evaluation of the literature, therefore, supports the fundamental conclusion that long-term HIV-1 viral protein exposure leads to a decreased dopaminergic state, which continues to persist despite the advent of cART. Thus, effective treatment of HIV-1-associated apathy/depression and neurocognitive impairments must focus on strategies for rectifying decreases in dopamine function.
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Affiliation(s)
| | | | | | | | | | - Rosemarie M. Booze
- Department of Psychology, University of South Carolina, Columbia, SC 29208, USA; (K.A.M.); (M.H.); (V.M.); (S.B.H.); (C.F.M.)
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17
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S-Equol mitigates motivational deficits and dysregulation associated with HIV-1. Sci Rep 2021; 11:11870. [PMID: 34088932 PMCID: PMC8178385 DOI: 10.1038/s41598-021-91240-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 05/17/2021] [Indexed: 02/04/2023] Open
Abstract
Motivational deficits (e.g., apathy) and dysregulation (e.g., addiction) in HIV-1 seropositive individuals, despite treatment with combination antiretroviral therapy, necessitates the development of innovative adjunctive therapeutics. S-Equol (SE), a selective estrogen receptor β agonist, has been implicated as a neuroprotective and/or neurorestorative therapeutic for HIV-1 associated neurocognitive disorders (HAND); its therapeutic utility for motivational alterations, however, has yet to be systematically evaluated. Thus, HIV-1 transgenic (Tg) and control animals were treated with either a daily oral dose of SE (0.2 mg) or vehicle and assessed in a series of tasks to evaluate goal-directed and drug-seeking behavior. First, at the genotypic level, motivational deficits in HIV-1 Tg rats treated with vehicle were characterized by a diminished reinforcing efficacy of, and sensitivity to, sucrose. Motivational dysregulation was evidenced by enhanced drug-seeking for cocaine relative to control animals treated with vehicle. Second, treatment with SE ameliorated both motivational deficits and dysregulation in HIV-1 Tg rats. Following a history of cocaine self-administration, HIV-1 Tg animals treated with vehicle exhibited lower levels of dendritic branching and a shift towards longer dendritic spines with decreased head diameter. Treatment with SE, however, led to long-term enhancements in dendritic spine morphology in HIV-1 Tg animals supporting a potential underlying basis by which SE exerts its therapeutic effects. Taken together, SE restored motivated behavior in the HIV-1 Tg rat, expanding the potential clinical utility of SE to include both neurocognitive and affective alterations.
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18
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Denton AR, Mactutus CF, Lateef AU, Harrod SB, Booze RM. Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage. J Neurovirol 2021; 27:403-421. [PMID: 34003469 PMCID: PMC8504184 DOI: 10.1007/s13365-021-00960-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 01/11/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.
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Affiliation(s)
- Adam R Denton
- Behavioral Neuroscience Laboratory, Department of Psychology, University of South Carolina, Columbia, South Carolina, USA
| | - Charles F Mactutus
- Behavioral Neuroscience Laboratory, Department of Psychology, University of South Carolina, Columbia, South Carolina, USA
| | - Almeera U Lateef
- Behavioral Neuroscience Laboratory, Department of Psychology, University of South Carolina, Columbia, South Carolina, USA
| | - Steven B Harrod
- Behavioral Neuroscience Laboratory, Department of Psychology, University of South Carolina, Columbia, South Carolina, USA
| | - Rosemarie M Booze
- Behavioral Neuroscience Laboratory, Department of Psychology, University of South Carolina, Columbia, South Carolina, USA.
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19
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Irollo E, Luchetta J, Ho C, Nash B, Meucci O. Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders. Cell Mol Life Sci 2021; 78:4283-4303. [PMID: 33585975 PMCID: PMC8164580 DOI: 10.1007/s00018-021-03785-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/14/2021] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.
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Affiliation(s)
- Elena Irollo
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA
| | - Jared Luchetta
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA
| | - Chunta Ho
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA
| | - Bradley Nash
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA
| | - Olimpia Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA. .,Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA. .,Center for Neuroimmunology and CNS Therapeutics, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA.
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Abstract
It has been well studied that the EcoHIV infected mouse model is of significant utility in investigating HIV associated neurological complications. Establishment of the EcoHIV infected rat model for studies of drug abuse and neurocognitive disorders, would be beneficial in the study of neuroHIV and HIV-1 associated neurocognitive disorders (HAND). In the present study, we demonstrate the successful creation of a rat model of active HIV infection using chimeric HIV (EcoHIV). First, the lentiviral construct of EcoHIV was packaged in cultured 293 FT cells for 48 hours. Then, the conditional medium was concentrated and titered. Next, we performed bilateral stereotaxic injections of the EcoHIV-EGFP into F344/N rat brain tissue. One week after infection, EGFP fluorescence signals were detected in the infected brain tissue, indicating that EcoHIV successfully induces an active HIV infection in rats. In addition, immunostaining for the microglial cell marker, Iba1, was performed. The results indicated that microglia were the predominant cell type harboring EcoHIV. Furthermore, EcoHIV rats exhibited alterations in temporal processing, a potential underlying neurobehavioral mechanism of HAND as well as synaptic dysfunction eight weeks after infection. Collectively, the present study extends the EcoHIV model of HIV-1 infection to the rat offering a valuable biological system to study HIV-1 viral reservoirs in the brain as well as HAND and associated comorbidities such as drug abuse.
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Affiliation(s)
- Hailong Li
- Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina
| | - Kristen A McLaurin
- Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina
| | - Charles F Mactutus
- Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina
| | - Rosemarie M Booze
- Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina;
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21
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Lin Y, He JJ, Sorensen R, Chang L. Unraveling neuroHIV in the Presence of Substance Use Disorders. J Neuroimmune Pharmacol 2020; 15:578-583. [PMID: 33215327 DOI: 10.1007/s11481-020-09967-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 10/26/2020] [Indexed: 01/08/2023]
Abstract
This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions.
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Affiliation(s)
- Yu Lin
- Division of Neuroscience and Behavior, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Johnny J He
- Department of Microbiology and Immunology, Chicago Medical School, and Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL, USA
| | - Roger Sorensen
- Division of Neuroscience and Behavior, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Linda Chang
- Department of Diagnostic Radiology and Nuclear Medicine, and Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA.
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