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HIV and Drugs of Abuse 2.0

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 17424

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Special Issue Editors

Dr. Maria Cecilia Garibaldi Marcondes

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Guest Editor

San Diego Biomedical Research Institute (SDBRI), 3525 John Hopkins Ct., San Diego, CA 92121, USA
Interests: neuroinflammation; neuro-immunemodulation; chronic inflammation; brain pathogenesis; HIV associated neurological disorders; drugs of abuse; innate immune response
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Marcus Kaul

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Guest Editor

Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA
Interests: neuroinflammation; neurodegenerative disease; host-pathogen interactions; HIV-1; drug abuse; innate immunity; microglia/macrophages; neuroprotection; stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Substance use disorders and HIV infection are long-standing public health concerns and frequent comorbidities. HIV continues to cause neurocognitive deficits in spite of highly effective anti-retroviral therapies that lead to viral suppression. Combined with the neurological consequences of drugs of abuse, HIV-associated neurological disorders present with a range of distinctive characteristics, and there is still no treatment available. Immune functions that are modulated by the actions of neurotransmitters released under the influence of abused drugs may be one reason for the aggravating effects of addiction on HIV-associated disorders in the central nervous system. Among the drugs of abuse, methamphetamine and other stimulants are highly detrimental due to associated risky behaviors, and due to their effects permanently altering neurotransmission. Given that HIV targets express neurotransmitter receptors, the brain environment in the context of substance use compromises the immune response, facilitating HIV infection of the brain. Polysubstance use is common in individuals with addictive behaviors, further complicating the picture. In this Special Issue of Viruses, we aim at integrating information derived from research with humans and animal models, as well as in cells of the immune system, thus providing a unique translational perspective of the clinical and mechanistic interactions between HIV and drugs of abuse that contribute to neurological disorders. Original work performed by interdisciplinary teams will be showcased.

Dr. Maria Cecilia Garibaldi Marcondes
Prof. Dr. Marcus Kaul
Guest Editors

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Keywords

substance use disorders
HIV
HAND
methamphetamine

Published Papers (10 papers)

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Research

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14 pages, 448 KiB

Open AccessArticle

Effects of Opioid Withdrawal on Psychobiology in People Living with HIV

by Igor Grant, Evgeny Krupitsky, Marina Vetrova, Anya Umlauf, Robert K. Heaton, Richard L. Hauger, Olga Toussova, Donald R. Franklin, Scott L. Letendre, George Woody, Elena Blokhina, Dmitry Lioznov and Edwin Zvartau

Viruses 2024, 16(1), 92; https://doi.org/10.3390/v16010092 - 06 Jan 2024

Viewed by 1010

Abstract

Objective: Many persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood. Method and participants: Study participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time. Results: HPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14. Conclusions: Worsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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12 pages, 3211 KiB

Open AccessArticle

Novel RNA-Seq Signatures Post-Methamphetamine and Oxycodone Use in a Model of HIV-Associated Neurocognitive Disorders

by Pranavi Athota, Nghi M. Nguyen, Victoria L. Schaal, Sankarasubramanian Jagadesan, Chittibabu Guda, Sowmya V. Yelamanchili and Gurudutt Pendyala

Viruses 2023, 15(9), 1948; https://doi.org/10.3390/v15091948 - 19 Sep 2023

Viewed by 1029

Abstract

In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU, including the identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-1 Transgenic (HIV-1 Tg) animal model to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone (oxy). A RNA-Seq analysis on the striatum—a brain region that is primarily targeted by both HIV and drugs of abuse—identified key differentially expressed markers post-METH and oxy exposure. Furthermore, ClueGO analysis and Ingenuity Pathway Analysis (IPA) revealed crucial molecular and biological functions associated with ATP-activated adenosine receptors, neuropeptide hormone activity, and the oxytocin signaling pathway to be altered between the different treatment groups. The current study further reveals the harmful effects of chronic PSU and HIV infection that can subsequently impact neurological outcomes in polysubstance users with HAND. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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26 pages, 5172 KiB

Open AccessArticle

MRP8/14 Is a Molecular Signature Triggered by Dopamine in HIV Latent Myeloid Targets That Increases HIV Transcription and Distinguishes HIV+ Methamphetamine Users with Detectable CSF Viral Load and Brain Pathology

by Liana V. Basova, Alexander Lindsey, Annemarie McGovern, Ashley Rosander, Violaine Delorme-Walker, Wael M. ElShamy, Ved Vasishtha Pendyala, Peter Jesse Gaskill, Ronald J. Ellis, Mariana Cherner, Jennifer E. Iudicello and Maria Cecilia Garibaldi Marcondes

Viruses 2023, 15(6), 1363; https://doi.org/10.3390/v15061363 - 13 Jun 2023

Cited by 1 | Viewed by 1648

Abstract

There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes’ transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users’ postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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19 pages, 3627 KiB

Open AccessArticle

The Synthetic Opioid Fentanyl Increases HIV Replication and Chemokine Co-Receptor Expression in Lymphocyte Cell Lines

by Janani Madhuravasal Krishnan, Ling Kong, Rebekah Karns, Mario Medvedovic, Kenneth E. Sherman and Jason T. Blackard

Viruses 2023, 15(4), 1027; https://doi.org/10.3390/v15041027 - 21 Apr 2023

Cited by 1 | Viewed by 2179

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. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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17 pages, 1845 KiB

Open AccessArticle

The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition

by Jeffrey M. Rogers, Jennifer E. Iudicello, Maria Cecilia G. Marcondes, Erin E. Morgan, Mariana Cherner, Ronald J. Ellis, Scott L. Letendre, Robert K. Heaton and Igor Grant

Viruses 2023, 15(3), 674; https://doi.org/10.3390/v15030674 - 03 Mar 2023

Cited by 2 | Viewed by 1704

Abstract

Objective: Methamphetamine and cannabis are two widely used substances among people living with HIV (PLWH). Whereas methamphetamine use has been found to worsen HIV-associated neurocognitive impairment, the effects of combined cannabis and methamphetamine use disorder on neurocognition in PLWH are not understood. In the present study, we aimed to determine the influence of these substance use disorders on neurocognition in PLWH and to explore if methamphetamine-cannabis effects interacted with HIV status. Method and Participants: After completing a comprehensive neurobehavioral assessment, PLWH (n = 472) were stratified by lifetime methamphetamine (M−/M+) and cannabis (C−/C+) DSM-IV abuse/dependence disorder into four groups: M−C− (n = 187), M−C+ (n = 68), M+C−, (n = 82), and M+C+ (n = 135). Group differences in global and domain neurocognitive performances and impairment were examined using multiple linear and logistic regression, respectively, while holding constant other covariates that were associated with study groups and/or cognition. Data from participants without HIV (n = 423) were added, and mixed-effect models were used to examine possible interactions between HIV and substance use disorders on neurocognition. Results: Compared with M+C+, M+C− performed worse on measures of executive functions, learning, memory, and working memory and were more likely to be classified as impaired in those domains. M−C− performed better than M+C+ on measures of learning and memory but worse than M−C+ on measures of executive functions, learning, memory, and working memory. Detectable plasma HIV RNA and nadir CD4 < 200 were associated with lower overall neurocognitive performance, and these effects were greater for M+C+ compared with M−C−. Conclusions: In PLWH, lifetime methamphetamine use disorder and both current and legacy markers of HIV disease severity are associated with worse neurocognitive outcomes. There was no evidence of an HIV × M+ interaction across groups, but neurocognition was most impacted by HIV among those with polysubstance use disorder (M+C+). Better performance by C+ groups is consistent with findings from preclinical studies that cannabis use may protect against methamphetamine’s deleterious effects. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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15 pages, 2027 KiB

Open AccessArticle

Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice

by Emaya M. Moss, Fakhri Mahdi, Charlie J. Worth and Jason J. Paris

Viruses 2023, 15(2), 424; https://doi.org/10.3390/v15020424 - 02 Feb 2023

Cited by 2 | Viewed by 1442

Abstract

Despite the benefits of combinatorial antiretroviral therapies (cART), virotoxic HIV proteins are still detectable within the central nervous system. Approximately half of all cART-treated patients contend with neurological impairments. The mechanisms underlying these effects likely involve virotoxic HIV proteins, including glycoprotein 120 (gp120). Glycoprotein-120 is neurotoxic due to its capacity to activate microglia. Corticosterone has been found to attenuate neuronal death caused by gp120-induced microglial cytokine production in vitro. However, the concentration-dependent effects of corticosterone on microglial activation states and the associated behavioral outcomes are unclear. Herein, we conducted parallel in vitro and in vivo studies to assess gp120-mediated effects on microglial activation, motor function, anxiety- and depression-like behavior, and corticosterone’s capacity to attenuate these effects. We found that gp120 activated microglia in vitro, and corticosterone attenuated this effect at an optimal concentration of 100 nM. Transgenic mice expressing gp120 demonstrated greater anxiety-like behavior on an elevated plus maze, and a greater duration of gp120 exposure was associated with motor deficits and anxiety-like behavior. Circulating corticosterone was lower in gp120-expressing males and diestrous females. Greater circulating corticosterone was associated with reduced anxiety-like behavior. These findings may demonstrate a capacity for glucocorticoids to attenuate gp120-mediated neuroinflammation and anxiety-like behavior. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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20 pages, 1546 KiB

Open AccessArticle

Virally Suppressed People Living with HIV Who Use Opioids Have Diminished Latency Reversal

by Binita Basukala, Sarah Rossi, Sally Bendiks, Natalia Gnatienko, Gregory Patts, Evgeny Krupitsky, Dmitry Lioznov, Kaku So-Armah, Manish Sagar, Christine Cheng and Andrew J. Henderson

Viruses 2023, 15(2), 415; https://doi.org/10.3390/v15020415 - 01 Feb 2023

Cited by 3 | Viewed by 2621

Abstract

Of the 12 million people who inject drugs worldwide, 13% live with HIV. Whether opioid use impacts HIV pathogenesis and latency is an outstanding question. To gain insight into whether opioid use influences the proviral landscape and latent HIV reservoir, we performed intact proviral DNA assays (IPDA) on peripheral blood mononuclear cells (PBMCs) from antiretroviral therapy (ART)-suppressed people living with HIV (PWH) with or without current opioid use. No differences were observed between PWH with and without opioid use in the frequency of HIV intact and defective proviral genomes. To evaluate the latent reservoir, we activated PBMCs from ART-suppressed PWH with or without opioid use and assessed the induction of HIV RNA. PWH using opioids had diminished responses to ex vivo HIV reactivation, suggesting a smaller reversible reservoir of HIV-1 latently infected cells. However, in vitro studies using primary CD4+ T cells treated with morphine showed no effect of opioids on HIV-1 infection, replication or latency establishment. The discrepancy in our results from in vitro and clinical samples suggests that while opioids may not directly impact HIV replication, latency and reactivation in CD4+ T cells, opioid use may indirectly shape the HIV reservoir in vivo by modulating general immune functions. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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Review

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15 pages, 1775 KiB

Open AccessReview

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

by Mattia Trunfio, Antoine Chaillon, Nadejda Beliakova-Bethell, Robert Deiss, Scott L. Letendre, Patricia K. Riggs, Niamh Higgins and Sara Gianella

Viruses 2023, 15(8), 1712; https://doi.org/10.3390/v15081712 - 09 Aug 2023

Cited by 1 | Viewed by 1291

Abstract

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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19 pages, 781 KiB

Open AccessReview

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

by Susmita Sil, Annadurai Thangaraj, Abiola Oladapo, Guoku Hu, Naseer A Kutchy, Ke Liao, Shilpa Buch and Palsamy Periyasamy

Viruses 2023, 15(1), 44; https://doi.org/10.3390/v15010044 - 23 Dec 2022

Cited by 3 | Viewed by 2931

Abstract

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. Full article

(This article belongs to the Special Issue HIV and Drugs of Abuse 2.0)

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