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Article: New Potential Axes of HIV Neuropathogenesis with Relevance to Biomarkers and Treatment.

Angelovich, Thomas A / Churchill, Melissa J / Wright, Edwina J / Brew, Bruce J

Current topics in behavioral neurosciences

2020 Volume 50, Page(s) 3–39

Abstract: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) affect approximately half of people living with HIV despite viral suppression with antiretroviral therapies and represent a major cause of morbidity. HAND affects activities of ...

Abstract	Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) affect approximately half of people living with HIV despite viral suppression with antiretroviral therapies and represent a major cause of morbidity. HAND affects activities of daily living including driving, using the Internet and, importantly, maintaining drug adherence. Whilst viral suppression with antiretroviral therapies (ART) has reduced the incidence of severe dementia, mild neurocognitive impairments continue to remain prevalent. The neuropathogenesis of HAND in the context of viral suppression remains ill-defined, but underlying neuroinflammation is likely central and driven by a combination of chronic intermittent low-level replication of whole virus or viral components, latent HIV infection, peripheral inflammation possibly from a disturbed gut microbiome or chronic cellular dysfunction in the central nervous system. HAND is optimally diagnosed by clinical assessment with imaging and neuropsychological testing, which can be difficult to perform in resource-limited settings. Thus, the identification of biomarkers of disease is a key focus of the field. In this chapter, recent advances in the pathogenesis of HAND and biomarkers that may aid its diagnosis and treatment will be discussed.
MeSH term(s)	Activities of Daily Living ; Biomarkers ; Central Nervous System ; HIV Infections/complications ; HIV Infections/drug therapy ; Humans ; Inflammation
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-02-11
Publishing country	Germany
Document type	Journal Article
ISSN	1866-3370
ISSN	1866-3370
DOI	10.1007/7854_2019_126
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Article ; Online: Non-Human Primate Models of HIV Brain Infection and Cognitive Disorders.

Byrnes, Sarah J / Angelovich, Thomas A / Busman-Sahay, Kathleen / Cochrane, Catherine R / Roche, Michael / Estes, Jacob D / Churchill, Melissa J

Viruses

2022 Volume 14, Issue 9

Abstract: Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions ... ...

Abstract	Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation.
MeSH term(s)	Animals ; Brain ; Cognition ; Cognitive Dysfunction ; HIV Infections/complications ; Inflammation ; Primates ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Immunodeficiency Virus ; Viral Load
Language	English
Publishing date	2022-09-09
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14091997
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Article: Non-Human Primate Models of HIV Brain Infection and Cognitive Disorders

Byrnes, Sarah J. / Angelovich, Thomas A. / Busman-Sahay, Kathleen / Cochrane, Catherine R. / Roche, Michael / Estes, Jacob D. / Churchill, Melissa J.

Viruses. 2022 Sept. 09, v. 14, no. 9

2022

Abstract	Human Immunodeficiency virus (HIV)-associated neurocognitive disorders are a major burden for people living with HIV whose viremia is stably suppressed with antiretroviral therapy. The pathogenesis of disease is likely multifaceted, with contributions from viral reservoirs including the brain, chronic and systemic inflammation, and traditional risk factors including drug use. Elucidating the effects of each element on disease pathogenesis is near impossible in human clinical or ex vivo studies, facilitating the need for robust and accurate non-human primate models. In this review, we describe the major non-human primate models of neuroHIV infection, their use to study the acute, chronic, and virally suppressed infection of the brain, and novel therapies targeting brain reservoirs and inflammation.
Keywords	Human immunodeficiency virus ; antiretroviral agents ; brain ; cognition ; humans ; inflammation ; pathogenesis ; risk ; therapeutics ; viremia
Language	English
Dates of publication	2022-0909
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14091997
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Understanding the mechanisms driving the spread of subtype C HIV-1.

Gartner, Matthew J / Roche, Michael / Churchill, Melissa J / Gorry, Paul R / Flynn, Jacqueline K

EBioMedicine

2020 Volume 53, Page(s) 102682

Abstract: Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is the most prevalent form of HIV-1 globally, accounting for approximately 50% of infections worldwide. C-HIV is the predominant and near-exclusive subtype in the low resource regions of India ...

Abstract	Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is the most prevalent form of HIV-1 globally, accounting for approximately 50% of infections worldwide. C-HIV is the predominant and near-exclusive subtype in the low resource regions of India and Southern Africa. Given the vast diversity of HIV-1 subtypes, it is curious as to why C-HIV constitutes such a large proportion of global infections. This enriched prevalence may be due to phenotypic differences between C-HIV isolates and other viral strains that permit enhanced transmission efficiency or, pathogenicity, or might due to the socio-demographics of the regions where C-HIV is endemic. Here, we compare the mechanisms of C-HIV pathogenesis to less prominent HIV-1 subtypes, including viral genetic and phenotypic characteristics, and host genetic variability, to understand whether evolutionary factors drove C-HIV to predominance.
MeSH term(s)	Evolution, Molecular ; Genome, Viral ; HIV Infections/epidemiology ; HIV Infections/transmission ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/pathogenicity ; HIV-1/physiology ; Humans ; Virus Replication
Language	English
Publishing date	2020-02-27
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2020.102682
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Article: Adaptation of the intact proviral DNA assay to a nanowell-based digital PCR platform.

Tumpach, Carolin / Cochrane, Catherine R / Kim, Youry / Ong, Jesslyn / Rhodes, Ajantha / Angelovich, Thomas A / Churchill, Melissa J / Lewin, Sharon R / Telwatte, Sushama / Roche, Michael

Journal of virus eradication

2023 Volume 9, Issue 2, Page(s) 100335

Abstract: Quantification of intact proviruses is a critical measurement in HIV cure studies ... ...

Abstract	Quantification of intact proviruses is a critical measurement in HIV cure studies both
Language	English
Publishing date	2023-06-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2868549-0
ISSN	2055-6659 ; 2055-6640
ISSN (online)	2055-6659
ISSN	2055-6640
DOI	10.1016/j.jve.2023.100335
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Article ; Online: Where does HIV hide? A focus on the central nervous system.

Churchill, Melissa / Nath, Avindra

Current opinion in HIV and AIDS

2013 Volume 8, Issue 3, Page(s) 165–169

Abstract: Purpose of review: To review the literature on infection and evolution of HIV within the brain in the context for understanding the nature of the brain reservoir and its consequences.: Recent findings: HIV-1 in the brain can evolve in separate ... ...

Abstract	Purpose of review: To review the literature on infection and evolution of HIV within the brain in the context for understanding the nature of the brain reservoir and its consequences. Recent findings: HIV-1 in the brain can evolve in separate compartments within macrophage/microglia and astrocytes. The virus adapts to the brain environment to infect these cells and brain-specific mutations can be found in nearly all genes of the virus. The virus evolves to become more neurovirulent. Summary: The brain is an ideal reservoir for the HIV. The brain is a relatively immune privileged site and the blood-brain barrier prevents easy access to antiretroviral drugs. Further, the virus infects resident macrophages and astrocytes which are long-lived cells and causes minimal cytopathology in these cells. Hence as we move towards developing strategies for eradication of the virus from the peripheral reservoirs, it is critical that we pay close attention to the virus in the brain and develop strategies for maintaining it in a latent state failure of which could result in dire consequences.
MeSH term(s)	Central Nervous System Viral Diseases/pathology ; Central Nervous System Viral Diseases/virology ; HIV Infections/pathology ; HIV Infections/virology ; Host-Pathogen Interactions ; Humans
Language	English
Publishing date	2013-02-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0b013e32835fc601
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Article ; Online: The role of oxidative stress in HIV-associated neurocognitive disorders.

Buckley, Sarah / Byrnes, Sarah / Cochrane, Catherine / Roche, Michael / Estes, Jacob D / Selemidis, Stavros / Angelovich, Thomas A / Churchill, Melissa J

Brain, behavior, & immunity - health

2021 Volume 13, Page(s) 100235

Abstract: HIV-associated neurocognitive disorders (HAND) are a leading cause of morbidity in up to 50% of individuals living with HIV, despite effective treatment with antiretroviral therapy (ART). Current evidence suggests that chronic inflammation associated ... ...

Abstract	HIV-associated neurocognitive disorders (HAND) are a leading cause of morbidity in up to 50% of individuals living with HIV, despite effective treatment with antiretroviral therapy (ART). Current evidence suggests that chronic inflammation associated with HIV is especially attributed to the dysregulated production of reactive oxygen species (ROS) that contribute to neurodegeneration and poor clinical outcomes. While ROS have beneficial effects in eliciting immune responses to infection, chronic ROS production causes damage to macromolecules such as DNA and lipids that has been linked to altered redox homeostasis associated with antioxidant dysregulation. As a result, this disruption in the balance between antioxidant-dependent mechanisms of ROS inactivation and ROS production by enzymes such as the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family, as well as from the electron transport chain of the mitochondria can result in oxidative stress. This is particularly relevant to the brain, which is exquisitely susceptible to oxidative stress due to its inherently high lipid concentration and ROS levels that have been linked to many neurodegenerative diseases that have similar stages of pathogenesis to HAND. In this review, we discuss the possible role and mechanisms of ROS production leading to oxidative stress that underpin HAND pathogenesis even when HIV is suppressed by current gold-standard antiretroviral therapies. Furthermore, we highlight that pathological ROS can serve as biomarkers for HIV-dependent HAND, and how manipulation of oxidative stress and antioxidant-dependent pathways may facilitate novel strategies for HIV cure.
Language	English
Publishing date	2021-02-28
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2021.100235
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Article ; Online: Strategies to target HIV-1 in the central nervous system.

Gray, Lachlan R / Brew, Bruce J / Churchill, Melissa J

Current opinion in HIV and AIDS

2016 Volume 11, Issue 4, Page(s) 371–375

Abstract: Purpose of review: To review current knowledge of viral reservoirs in the central nervous system (CNS) and identify the CNS-specific barriers and strategies to cure human immunodeficiency virus type 1 (HIV-1) within the brain.: Recent findings: The ... ...

Abstract	Purpose of review: To review current knowledge of viral reservoirs in the central nervous system (CNS) and identify the CNS-specific barriers and strategies to cure human immunodeficiency virus type 1 (HIV-1) within the brain. Recent findings: The cumulative data of HIV-1 infection of the CNS support the ability of the CNS to act as a viral reservoir for HIV-1. The HIV-1 viral strains found in the CNS are distinct to those found in other parts of the body. These differences have been well documented for env and also extend to the viral promoter, the long terminal repeat, and influence the ability of the virus to replicate, establish latency and respond to latency-reversing agents (LRAs). In addition, the bioavailability and activity of LRAs and antiretrovirals within the CNS suggest altered properties compared with the blood, which may influence their effectiveness. Selected LRAs were shown to have reduced effectiveness against CNS-derived viral strains compared with blood-derived strains from the same patients. Finally, altered immune surveillance within the CNS may also interfere with the efficiency of cure strategies within this compartment. Summary: Together, these data suggest that the CNS viral reservoir is unique and presents a distinct set of challenges that need to be overcome to ensure successful viral elimination within this compartment. Future studies will need to develop CNS-active LRAs and biomarkers to enable monitoring and evaluation of treatment outcomes within the CNS during HIV-1 cure clinical trials.
MeSH term(s)	Biomedical Research/trends ; Central Nervous System/virology ; Drug Therapy/methods ; HIV Infections/virology ; HIV-1/physiology ; Humans ; Virus Latency
Language	English
Publishing date	2016-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000278
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Article: Modular Lentiviral Vectors for Highly Efficient Transgene Expression in Resting Immune Cells

Fichter, Christina / Aggarwal, Anupriya / Wong, Andrew Kam Ho / McAllery, Samantha / Mathivanan, Vennila / Hao, Bailey / MacRae, Hugh / Churchill, Melissa J. / Gorry, Paul R. / Roche, Michael / Gray, Lachlan R. / Turville, Stuart

Viruses. 2021 June 18, v. 13, no. 6

2021

Abstract: Gene/cell therapies are promising strategies for the many presently incurable diseases. A key step in this process is the efficient delivery of genes and gene-editing enzymes to many cell types that may be resistant to lentiviral vector transduction. ... ...

Abstract	Gene/cell therapies are promising strategies for the many presently incurable diseases. A key step in this process is the efficient delivery of genes and gene-editing enzymes to many cell types that may be resistant to lentiviral vector transduction. Herein we describe tuning of a lentiviral gene therapy platform to focus on genetic modifications of resting CD4⁺ T cells. The motivation for this was to find solutions for HIV gene therapy efforts. Through selection of the optimal viral envelope and further modification to its expression, lentiviral fusogenic delivery into resting CD4⁺ T cells exceeded 80%, yet Sterile Alpha Motif and HD domain 1 (SAMHD1) dependent and independent intracellular restriction factors within resting T cells then dominate delivery and integration of lentiviral cargo. Overcoming SAMHD1-imposed restrictions, only observed up to 6-fold increase in transduction, with maximal gene delivery and expression of 35%. To test if the biologically limiting steps of lentiviral delivery are reverse transcription and integration, we re-engineered lentiviral vectors to simply express biologically active mRNA to direct transgene expression in the cytoplasm. In this setting, we observed gene expression in up to 65% of resting CD4⁺ T cells using unconcentrated MS2 lentivirus-like particles (MS2-LVLPs). Taken together, our findings support a gene therapy platform that could be readily used in resting T cell gene editing.
Keywords	cytoplasm ; gene editing ; gene expression ; gene therapy ; gene transfer ; genes ; motivation ; reverse transcription
Language	English
Dates of publication	2021-0618
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13061170
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Article: Lipidomic dataset of plasma from patients infected with wild type and nef-deficient HIV-1 strain

Meikle, Peter / Low, Hann / Churchill, Melissa J. / Bukrinsky, Michael / Sviridov, Dmitri

Data in Brief. 2016 Mar., v. 6

2016

Abstract: Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative ...

Abstract	Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative lipidomic analysis (330 lipid species) of plasma samples from HIV-negative subjects, patients infected with WT HIV-1 strain and patients infected with nef-deficient strain of HIV-1. We determine which effects of HIV on plasma lipidome are explained by the presence of nef. The data can be used to evaluate cardiovascular risk in HIV disease and to assess the role of nef in HIV-induced disturbances in systemic lipid metabolism. The full impact of nef deficiency on lipid and lipoprotein metabolism in HIV-infected patients is presented in the accompanying study “Lipid Metabolism in Patients Infected with Nef-deficient HIV-1 Strain” [1].
Keywords	HIV infections ; cholesterol metabolism ; data collection ; lipidomics ; lipoprotein metabolism ; risk
Language	English
Dates of publication	2016-03
Size	p. 168-175.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2786545-9
ISSN	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2015.11.067
Database	NAL-Catalogue (AGRICOLA)

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