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The Impact of Opioids, Methamphetamine, and Antiviral Compounds on Mechanisms of HIV Pathogenesis in Human Macrophages.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	The Impact of Opioids, Methamphetamine, and Antiviral Compounds on Mechanisms of HIV Pathogenesis in Human Macrophages./
Author:	Barbaro, John M.
Description:	1 online resource (407 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-03, Section: B.
Contained By:	Dissertations Abstracts International84-03B.
Subject:	Pathology. -
Online resource:	click for full text (PQDT)
ISBN:	9798845421739

The Impact of Opioids, Methamphetamine, and Antiviral Compounds on Mechanisms of HIV Pathogenesis in Human Macrophages.
Barbaro, John M.

The Impact of Opioids, Methamphetamine, and Antiviral Compounds on Mechanisms of HIV Pathogenesis in Human Macrophages. - 1 online resource (407 pages)

Source: Dissertations Abstracts International, Volume: 84-03, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2024.

Includes bibliographical references

Approximately 38 million people worldwide are living with HIV. People with HIV (PWH) have improved quality of life due to antiretroviral therapy (ART), which effectively suppresses HIV replication. Despite ART, many PWH experience debilitating comorbidities. One such comorbidity is HIV-Neurocognitive Impairment (HIV-NCI), which affects ~15-40% of PWH despite peripheral viral suppression by ART. HIV-NCI is a spectrum of psychomotor and cognitive deficits that increases mortality risk. There is no specific therapy for HIV-NCI for PWH taking ART. The HIV epidemic is impacted by substance use, which has been increasing dramatically in the United States during the 2000's. Two substances that have been shown to impact neurocognitive function in PWH are methamphetamine (meth) and opioids. The molecular mechanisms by which meth and opioids impact HIV neuropathogenesis in the context of ART remain largely unknown. Meth or opioids can dysregulate homeostatic functions in the HIV-infected CNS. Restoring these functions is critical to mitigate neurocognitive decline in substance users with HIV. Myeloid cells, monocyte derived macrophages (MDM) and microglia, harbor HIV in the brains of PWH-even in those taking ART. These cells become infected due, in part, to the transmigration of mature HIV-infected monocytes across the blood-brainbarrier into the CNS. Monocytes can differentiate into long-lived MDM. HIV infection of MDM dysregulates processes that mediate neuroinflammation and damage to parenchymal cells including neurons and astrocytes. These processes include phagocytosis of neurotoxic proteins and apoptotic cells, elaboration of injurious reactive oxygen species (ROS), and regulation of macroautophagy. Macroautophagy is a catabolic process that degrades damaged macromolecules and organelles for energy for the cell, both in bulk and selectively, which are recycled to form new structures. Autophagic activity is manipulated by HIV in infected macrophages to promote survival and output of viral particles. Studies have demonstrated that autophagy can, in part, regulate other myeloid cell functions that mediate HIV neuropathogenesis including phagocytosis, ROS levels, and inflammatory cytokine release. We hypothesized that meth or opioids, specifically morphine, dysregulate phagocytosis, ROS levels, and autophagy in primary human MDM to increase neuropathogenesis. In HIV-infected primary human MDM, meth with or without ART inhibited phagocytosis of aggregated amyloid-β, increased ROS, and induced autophagy while inhibiting its completion. ART alone, consisting of tenofovir, emtricitabine, and dolutegravir tested at concentrations consistent with average CSF levels, had negligible effects. When we inhibited lysosomal degradation of autophagic substrates, ROS were increased more in response to meth. By mass spectrometry, meth caused proteomic changes associated with host-virus interactions and several neurodegenerative diseases. We also successfully cultured human microglia from hematopoietic progenitor stem cells. In preliminary studies, meth induced autophagy in uninfected microglia and inhibited phagocytosis of amyloid-β in HIV-infected microglia, as in MDM. In our morphine studies, we used an ART cocktail of tenofovir, emtricitabine, and raltegravir at concentrations commonly tested in model systems. In both uninfected and HIV-infected MDM, morphine, with or without ART, increased phagocytosis of various substrates and increased ROS levels-indicative of cell activation. ART alone increased phagocytosis, as well. We also found that morphine, with or without ART, induced autophagy in uninfected MDM. In HIV-infected MDM, there was additional autophagy inhibition that compromised degradation of aggregated proteins (aggrephagy) and mitochondria (mitophagy). By mass spectrometry, morphine caused differential expression of proteins involved in other processes that may also enhance neuropathogenesis including ER quality control and VEGFR2 signaling, which we validated by Western blotting. Differentially expressed proteins that contribute to functional compromise may be therapeutic targets to reduce neurocognitive deficits in PWH using meth or opioids. Despite the success of ART, some antiretroviral agents contribute to off-target negative effects in cells unrelated to viral suppression. Compounds more similar in structure to those that occur naturally during viral infection may maintain HIV suppression without producing undesirable effects. We determined the anti-HIV activity of ddhCTP. This compound is produced in response to interferon signaling during infection with several viruses, and it reduces flavivirus replication in immortalized cell lines. In primary human MDM, we found that two novel ddhCTP prodrugs, IB-ddhC and ProTide-ddhC, inhibited HIV replication to near undetectable levels at the highest tested dose. Both prodrugs increased intracellular levels of ddhCTP and were non-toxic. These studies underscore IB-ddhC and ProTide-ddhC as promising ART candidates to evaluate in vivo efficacy in combination with existing drugs and the extent of their offtarget effects relative to existing regimens for prevention and treatment of HIV infection. Collectively, our data underscore the impact of drug use and antiviral compounds on myeloid cells that harbor HIV with prospects for therapeutic intervention to ameliorate functional dysregulation.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798845421739Subjects--Topical Terms:

668553
Pathology.
Subjects--Index Terms:

AntiretroviralsIndex Terms--Genre/Form:

554714
Electronic books.

The Impact of Opioids, Methamphetamine, and Antiviral Compounds on Mechanisms of HIV Pathogenesis in Human Macrophages.
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Meth or opioids can dysregulate homeostatic functions in the HIV-infected CNS. Restoring these functions is critical to mitigate neurocognitive decline in substance users with HIV. Myeloid cells, monocyte derived macrophages (MDM) and microglia, harbor HIV in the brains of PWH-even in those taking ART. These cells become infected due, in part, to the transmigration of mature HIV-infected monocytes across the blood-brainbarrier into the CNS. Monocytes can differentiate into long-lived MDM. HIV infection of MDM dysregulates processes that mediate neuroinflammation and damage to parenchymal cells including neurons and astrocytes. These processes include phagocytosis of neurotoxic proteins and apoptotic cells, elaboration of injurious reactive oxygen species (ROS), and regulation of macroautophagy. Macroautophagy is a catabolic process that degrades damaged macromolecules and organelles for energy for the cell, both in bulk and selectively, which are recycled to form new structures. Autophagic activity is manipulated by HIV in infected macrophages to promote survival and output of viral particles. Studies have demonstrated that autophagy can, in part, regulate other myeloid cell functions that mediate HIV neuropathogenesis including phagocytosis, ROS levels, and inflammatory cytokine release. We hypothesized that meth or opioids, specifically morphine, dysregulate phagocytosis, ROS levels, and autophagy in primary human MDM to increase neuropathogenesis. In HIV-infected primary human MDM, meth with or without ART inhibited phagocytosis of aggregated amyloid-β, increased ROS, and induced autophagy while inhibiting its completion. ART alone, consisting of tenofovir, emtricitabine, and dolutegravir tested at concentrations consistent with average CSF levels, had negligible effects. When we inhibited lysosomal degradation of autophagic substrates, ROS were increased more in response to meth. By mass spectrometry, meth caused proteomic changes associated with host-virus interactions and several neurodegenerative diseases. We also successfully cultured human microglia from hematopoietic progenitor stem cells. In preliminary studies, meth induced autophagy in uninfected microglia and inhibited phagocytosis of amyloid-β in HIV-infected microglia, as in MDM. In our morphine studies, we used an ART cocktail of tenofovir, emtricitabine, and raltegravir at concentrations commonly tested in model systems. In both uninfected and HIV-infected MDM, morphine, with or without ART, increased phagocytosis of various substrates and increased ROS levels-indicative of cell activation. ART alone increased phagocytosis, as well. We also found that morphine, with or without ART, induced autophagy in uninfected MDM. In HIV-infected MDM, there was additional autophagy inhibition that compromised degradation of aggregated proteins (aggrephagy) and mitochondria (mitophagy). By mass spectrometry, morphine caused differential expression of proteins involved in other processes that may also enhance neuropathogenesis including ER quality control and VEGFR2 signaling, which we validated by Western blotting. Differentially expressed proteins that contribute to functional compromise may be therapeutic targets to reduce neurocognitive deficits in PWH using meth or opioids. Despite the success of ART, some antiretroviral agents contribute to off-target negative effects in cells unrelated to viral suppression. Compounds more similar in structure to those that occur naturally during viral infection may maintain HIV suppression without producing undesirable effects. We determined the anti-HIV activity of ddhCTP. This compound is produced in response to interferon signaling during infection with several viruses, and it reduces flavivirus replication in immortalized cell lines. In primary human MDM, we found that two novel ddhCTP prodrugs, IB-ddhC and ProTide-ddhC, inhibited HIV replication to near undetectable levels at the highest tested dose. Both prodrugs increased intracellular levels of ddhCTP and were non-toxic. These studies underscore IB-ddhC and ProTide-ddhC as promising ART candidates to evaluate in vivo efficacy in combination with existing drugs and the extent of their offtarget effects relative to existing regimens for prevention and treatment of HIV infection. Collectively, our data underscore the impact of drug use and antiviral compounds on myeloid cells that harbor HIV with prospects for therapeutic intervention to ameliorate functional dysregulation.
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