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Article ; Online: Methamphetamine induces transcriptional changes in cultured HIV-infected mature monocytes that may contribute to HIV neuropathogenesis.

Chilunda, Vanessa / Weiselberg, Jessica / Martinez-Meza, Samuel / Mhamilawa, Lwidiko E / Cheney, Laura / Berman, Joan W

2022 Volume 13, Page(s) 952183

Abstract: HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development ... ...

Abstract	HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation. Substance use disorders in PWH, including the use of methamphetamine (meth), can exacerbate HIV neuropathogenesis. We characterized the effects of meth on the transcriptional profile of HIV-infected mature monocytes using RNA-sequencing. We found that meth mediated an upregulation of gene transcripts related to viral infection, cell adhesion, cytoskeletal arrangement, and extracellular matrix remodeling. We also identified downregulation of several gene transcripts involved in pathogen recognition, antigen presentation, and oxidative phosphorylation pathways. These transcriptomic changes suggest that meth increases the infiltration of mature monocytes that have a migratory phenotype into the CNS, contributing to dysregulated inflammatory responses and viral reservoir establishment and persistence, both of which contribute to neuronal damage. Overall, our results highlight potential molecules that may be targeted for therapy to limit the effects of meth on HIV neuropathogenesis.
MeSH term(s)	HIV Infections ; Humans ; Macrophages/metabolism ; Methamphetamine/pharmacology ; Monocytes ; Quality of Life
Chemical Substances	Methamphetamine (44RAL3456C)
Language	English
Publishing date	2022-08-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.952183
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The impact of substance abuse on HIV-mediated neuropathogenesis in the current ART era.

Chilunda, Vanessa / Calderon, Tina M / Martinez-Aguado, Pablo / Berman, Joan W

Brain research

2019 Volume 1724, Page(s) 146426

Abstract: Approximately 37 million people worldwide are infected with human immunodeficiency virus (HIV). One highly significant complication of HIV infection is the development of HIV-associated neurocognitive disorders (HAND) in 15-55% of people living with HIV ( ...

Abstract	Approximately 37 million people worldwide are infected with human immunodeficiency virus (HIV). One highly significant complication of HIV infection is the development of HIV-associated neurocognitive disorders (HAND) in 15-55% of people living with HIV (PLWH), that persists even in the antiretroviral therapy (ART) era. The entry of HIV into the central nervous system (CNS) occurs within 4-8 days after peripheral infection. This establishes viral reservoirs that may persist even in the presence of ART. Once in the CNS, HIV infects resident macrophages, microglia, and at low levels, astrocytes. In response to chronic infection and cell activation within the CNS, viral proteins, inflammatory mediators, and host and viral neurotoxic factors produced over extended periods of time result in neuronal injury and loss, cognitive deficits and HAND. Substance abuse is a common comorbidity in PLWH and has been shown to increase neuroinflammation and cognitive disorders. Additionally, it has been associated with poor ART adherence, and increased viral load in the cerebrospinal fluid (CSF), that may also contribute to increased neuroinflammation and neuronal injury. Studies have examined mechanisms that contribute to neuroinflammation and neuronal damage in PLWH, and how substances of abuse exacerbate these effects. This review will focus on how substances of abuse, with an emphasis on methamphetamine (meth), cocaine, and opioids, impact blood brain barrier (BBB) integrity and transmigration of HIV-infected and uninfected monocytes across the BBB, as well as their effects on monocytes/macrophages, microglia, and astrocytes within the CNS. We will also address how these substances of abuse may contribute to HIV-mediated neuropathogenesis in the context of suppressive ART. Additionally, we will review the effects of extracellular dopamine, a neurotransmitter that is increased in the CNS by substances of abuse, on HIV neuropathogenesis and how this may contribute to neuroinflammation, neuronal insult, and HAND in PLWH with active substance use. Lastly, we will discuss some potential therapies to limit CNS inflammation and damage in HIV-infected substance abusers.
MeSH term(s)	AIDS Dementia Complex/physiopathology ; Astrocytes/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Central Nervous System Diseases/physiopathology ; HIV Infections/complications ; HIV Infections/physiopathology ; Humans ; Macrophages/metabolism ; Microglia/metabolism ; Monocytes/metabolism ; Substance-Related Disorders/metabolism ; Substance-Related Disorders/physiopathology ; Viral Load
Language	English
Publishing date	2019-08-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2019.146426
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Article ; Online: Proportion of Hospitalizations Preventable with Increased Oral SARS-CoV-2 Antiviral Treatment

Levy, Matthew E. / Chilunda, Vanessa / Heaton, Phillip R. / Grzymski, Joseph / Pawloski, Pamala A. / Goldman, Jason D. / Luo, Shishi

medRxiv

Abstract: We estimated the proportion of hospitalizations that could have been averted had all eligible high-risk adults with SARS-CoV-2 infection in a clinical cohort been treated with an oral SARS-CoV-2 antiviral agent early in infection. Among 3,037 patients ... ...

Abstract	We estimated the proportion of hospitalizations that could have been averted had all eligible high-risk adults with SARS-CoV-2 infection in a clinical cohort been treated with an oral SARS-CoV-2 antiviral agent early in infection. Among 3,037 patients with risk factors for progressing to severe COVID-19, 946 (31.1%) received an oral antiviral prescription (834 nirmatrelvir and 112 molnupiravir). Only 3.0% of treated patients vs 9.1% of untreated patients were hospitalized (adjusted risk ratio [RR]=0.27; 95% confidence interval [CI]: 0.18-0.41). If all patients had been treated, an estimated 63.3% (95% CI: 50.4-75.1) of hospitalizations within 30 days could have been prevented. This finding is attributed to large gaps in treatment and a strong protective association of antiviral treatment with subsequent hospitalization.
Keywords	covid19
Language	English
Publishing date	2023-12-21
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2023.12.19.23300241
Database	COVID19

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Article ; Online: SARS-CoV-2 Antiviral Prescribing Gaps Among Non-Hospitalized High-Risk Adults.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2024

Abstract: Within a multi-state clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among non-hospitalized SARS-CoV-2-infected patients with risk factors for severe COVID-19. Among 3,247 adults, only 31.9% were ... ...

Abstract	Within a multi-state clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among non-hospitalized SARS-CoV-2-infected patients with risk factors for severe COVID-19. Among 3,247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers.
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciad796
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Article ; Online: Transcriptional Changes in CD16+ Monocytes May Contribute to the Pathogenesis of COVID-19.

Chilunda, Vanessa / Martinez-Aguado, Pablo / Xia, Li C / Cheney, Laura / Murphy, Aniella / Veksler, Veronica / Ruiz, Vanessa / Calderon, Tina M / Berman, Joan W

Frontiers in immunology

2021 Volume 12, Page(s) 665773

Abstract: The COVID-19 pandemic has caused more than three million deaths globally. The severity of the disease is characterized, in part, by a dysregulated immune response. CD16+ monocytes are innate immune cells involved in inflammatory responses to viral ... ...

Abstract	The COVID-19 pandemic has caused more than three million deaths globally. The severity of the disease is characterized, in part, by a dysregulated immune response. CD16+ monocytes are innate immune cells involved in inflammatory responses to viral infections, and tissue repair, among other functions. We characterized the transcriptional changes in CD16+ monocytes from PBMC of people with COVID-19, and from healthy individuals using publicly available single cell RNA sequencing data. CD16+ monocytes from people with COVID-19 compared to those from healthy individuals expressed transcriptional changes indicative of increased cell activation, and induction of a migratory phenotype. We also analyzed COVID-19 cases based on severity of the disease and found that mild cases were characterized by upregulation of interferon response and MHC class II related genes, whereas the severe cases had dysregulated expression of mitochondrial and antigen presentation genes, and upregulated inflammatory, cell movement, and apoptotic gene signatures. These results suggest that CD16+ monocytes in people with COVID-19 contribute to a dysregulated host response characterized by decreased antigen presentation, and an elevated inflammatory response with increased monocytic infiltration into tissues. Our results show that there are transcriptomic changes in CD16+ monocytes that may impact the functions of these cells, contributing to the pathogenesis and severity of COVID-19.
MeSH term(s)	Adult ; Aged ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/metabolism ; COVID-19/virology ; Case-Control Studies ; Cytokines/genetics ; Cytokines/metabolism ; Female ; GPI-Linked Proteins/metabolism ; Gene Expression Profiling ; Host-Pathogen Interactions ; Humans ; Inflammation Mediators/metabolism ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Male ; Middle Aged ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Monocytes/immunology ; Monocytes/metabolism ; Monocytes/virology ; RNA-Seq ; Receptors, IgG/metabolism ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Severity of Illness Index ; Single-Cell Analysis ; Transcription, Genetic ; Transcriptome ; Young Adult
Chemical Substances	Apoptosis Regulatory Proteins ; Cytokines ; FCGR3B protein, human ; GPI-Linked Proteins ; Inflammation Mediators ; Interferon Regulatory Factors ; Mitochondrial Proteins ; Receptors, IgG
Language	English
Publishing date	2021-05-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.665773
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Article ; Online: The Effects of Opioids on HIV Neuropathogenesis.

Murphy, Aniella / Barbaro, John / Martínez-Aguado, Pablo / Chilunda, Vanessa / Jaureguiberry-Bravo, Matias / Berman, Joan W

Frontiers in immunology

2019 Volume 10, Page(s) 2445

Abstract: HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or ... ...

Abstract	HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or treatments for HAND. Given the national opioid epidemic, as well as illegal and prescription use of opioid drugs among PLWH, it is critical to characterize the molecular interactions between HIV and opioids in cells of the CNS. It is also important to study the role of opioid substitution therapies in the context of HIV and CNS damage
MeSH term(s)	Analgesics, Opioid/adverse effects ; Animals ; Antiretroviral Therapy, Highly Active ; Astrocytes/drug effects ; Astrocytes/immunology ; Astrocytes/metabolism ; Blood-Brain Barrier/metabolism ; Disease Susceptibility ; HIV Infections/complications ; HIV Infections/drug therapy ; HIV Infections/virology ; Humans ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Models, Biological ; Monocytes/drug effects ; Monocytes/immunology ; Monocytes/metabolism ; Nervous System Diseases/diagnosis ; Nervous System Diseases/epidemiology ; Nervous System Diseases/etiology ; Nervous System Diseases/therapy ; Opioid-Related Disorders/complications ; Opioid-Related Disorders/epidemiology ; Opioid-Related Disorders/therapy ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2019-10-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.02445
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Article ; Online: XBB.1.5 mRNA COVID-19 Vaccination and Inpatient or Emergency Department Visits Among Adults Infected with SARS-CoV-2 JN.1 and XBB-Lineage Variants

medRxiv

Abstract: Within a multi-state viral genomic surveillance program, we conducted a case-control analysis comparing prior receipt of XBB.1.5-adapted mRNA vaccination between SARS-CoV-2-infected adults with inpatient/ED visits (proxy for severe illness) vs outpatient ...

Abstract	Within a multi-state viral genomic surveillance program, we conducted a case-control analysis comparing prior receipt of XBB.1.5-adapted mRNA vaccination between SARS-CoV-2-infected adults with inpatient/ED visits (proxy for severe illness) vs outpatient visits. Among 6,551 patients from September 2023-January 2024, 6.1% with inpatient/ED visits vs 12.0% with outpatient visits had received XBB.1.5 vaccination (aOR=0.41; 95% CI: 0.32-0.53). This protective association was weaker among JN.1 (aOR=0.62; 95% CI: 0.40-0.96) vs XBB-lineage (aOR=0.28; 95% CI: 0.18-0.43) variant infections (interaction, p=0.003). XBB.1.5 vaccination was also protective specifically compared to BA.4/BA.5-adapted mRNA vaccination (aOR=0.60; 95% CI: 0.45-0.79). XBB.1.5 vaccines protect against severe illness, but protection may be weaker against JN.1 vs XBB-lineage variants.
Keywords	covid19
Language	English
Publishing date	2024-03-06
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2024.03.05.24303796
Database	COVID19

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Article ; Online: In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells.

JCI insight

2022 Volume 7, Issue 21

Abstract: HIV-specific chimeric antigen receptor-T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. ... ...

Abstract	HIV-specific chimeric antigen receptor-T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell-like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).
MeSH term(s)	Animals ; Mice ; CD4-Positive T-Lymphocytes ; HIV Infections/drug therapy ; HIV-1 ; Leukocytes, Mononuclear ; Receptors, Chimeric Antigen ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic
Chemical Substances	Receptors, Chimeric Antigen
Language	English
Publishing date	2022-11-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.161698
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: In vivo killing of primary HIV-infected cells by peripheral-injected early memory–enriched anti-HIV duoCAR T cells

JCI Insight, Vol 7, Iss

2022 Volume 21

Abstract: HIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. ... ...

Abstract	HIV-specific chimeric antigen receptor–T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell–like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).
Keywords	AIDS/HIV ; Therapeutics ; Medicine ; R
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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