Crucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

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New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System

Cells ◽

10.3390/cells8101245 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1245 ◽

Cited By ~ 10

Author(s):

Victoria Rojas-Celis ◽

Fernando Valiente-Echeverría ◽

Ricardo Soto-Rifo ◽

Daniela Toro-Ascuy

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cell Types ◽

Latent Reservoir ◽

People Living With Hiv ◽

Viral Load Suppression ◽

The Central Nervous System ◽

Immunodeficiency Syndrome ◽

Living With Hiv ◽

Hiv 1

Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells.

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Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus

AIDS ◽

10.1097/01.aids.0000166090.31693.aa ◽

2005 ◽

Vol 19 (7) ◽

pp. 675-684 ◽

Cited By ~ 35

Author(s):

Evan J Burkala ◽

Jun He ◽

John T West ◽

Charles Wood ◽

Carol K Petito

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Choroid Plexus ◽

The Central Nervous System ◽

Hiv 1

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Dual antiretroviral therapies are effective and safe regimens in the central nervous system of neurologically symptomatic people living with HIV

AIDS ◽

10.1097/qad.0000000000002601 ◽

2020 ◽

Vol 34 (13) ◽

pp. 1899-1906 ◽

Cited By ~ 1

Author(s):

Mattia Trunfio ◽

Walter Rugge ◽

Lorenzo Mighetto ◽

Daniela Vai ◽

Cristiana Atzori ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

People Living With Hiv ◽

Antiretroviral Therapies ◽

The Central Nervous System ◽

Living With Hiv

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Potential neuroprotective role of astroglial exosomes against smoking-induced oxidative stress and HIV-1 replication in the central nervous system

Expert Opinion on Therapeutic Targets ◽

10.1080/14728222.2018.1501473 ◽

2018 ◽

Vol 22 (8) ◽

pp. 703-714 ◽

Cited By ~ 12

Author(s):

Sabina Ranjit ◽

Benjamin J. Patters ◽

Kelli A. Gerth ◽

Sanjana Haque ◽

Sanjeev Choudhary ◽

...

Keyword(s):

Oxidative Stress ◽

Central Nervous System ◽

Nervous System ◽

The Central Nervous System ◽

Hiv 1

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

Cells ◽

10.3390/cells9081857 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1857

Author(s):

Susmita Sil ◽

Fang Niu ◽

Ernest T. Chivero ◽

Seema Singh ◽

Palsamy Periyasamy ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Drug Abuse ◽

Current Knowledge ◽

Premature Aging ◽

Inflammasome Activation ◽

People Living With Hiv ◽

Abused Drugs ◽

Hiv 1

Despite the effectiveness of combined antiretroviral therapy (cART) in suppressing virus replication, chronic inflammation remains one of the cardinal features intersecting HIV-1, cART, drug abuse, and likely contributes to the accelerated neurocognitive decline and aging in people living with HIV-1 (PLWH) that abuse drugs. It is also estimated that ~30–60% of PLWH on cART develop cognitive deficits associated with HIV-1-associated neurocognitive disorders (HAND), with symptomatology ranging from asymptomatic to mild, neurocognitive impairments. Adding further complexity to HAND is the comorbidity of drug abuse in PLWH involving activated immune responses and the release of neurotoxins, which, in turn, mediate neuroinflammation. Premature or accelerated aging is another feature of drug abusing PLWH on cART regimes. Emerging studies implicate the role of HIV-1/HIV-1 proteins, cART, and abused drugs in altering the inflammasome signaling in the central nervous system (CNS) cells. It is thus likely that exposure of these cells to HIV-1/HIV-1 proteins, cART, and/or abused drugs could have synergistic/additive effects on the activation of inflammasomes, in turn, leading to exacerbated neuroinflammation, ultimately resulting in premature aging referred to as “inflammaging” In this review, we summarize the current knowledge of inflammasome activation, neuroinflammation, and aging in central nervous system (CNS) cells such as microglia, astrocytes, and neurons in the context of HIV-1 and drug abuse.

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A rare case of HIV CNS escape in a patient previously considered a viral controller

International Journal of STD & AIDS ◽

10.1177/0956462420922452 ◽

2020 ◽

Vol 31 (7) ◽

pp. 694-698

Author(s):

Jessica Magid-Bernstein ◽

Chu-Yueh Guo ◽

Felicia C Chow ◽

Kiran T Thakur

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Hiv Infection ◽

Viral Suppression ◽

Cns Infection ◽

People Living With Hiv ◽

Hiv Rna ◽

Perinatal Hiv ◽

The Central Nervous System ◽

Living With Hiv

Human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels generally remain undetectable in the cerebrospinal fluid of people living with HIV with peripheral viral suppression. Secondary HIV central nervous system (CNS) escape refers to the rare independent replication of HIV RNA in the central nervous system despite peripheral viral suppression that occurs in the setting of a concomitant non-HIV infection. We describe here a young man with perinatal HIV infection considered a viral controller who developed secondary HIV CNS escape in the setting of a presumed fungal CNS infection.

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HIV-associated tuberculosis with central nervous system involvement (literature review)

MedAlliance ◽

10.36422/23076348-2020-8-4-25-31 ◽

2020 ◽

Vol 8 (4) ◽

pp. 25-31

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Central Nervous System Involvement ◽

High Viral Load ◽

Future Research ◽

People Living With Hiv ◽

Associated Lesions ◽

The Central Nervous System ◽

Living With Hiv ◽

Inflammatory Syndrome

Tuberculosis is one of the most common comorbidities in people living with HIV. Immunodeficiency caused by HIV contributes to the development of tuberculosis or aggra-vates the existing disease. At the same time, TB on the background of a pronounced immunodeficiency caused by HIV is more severe than in immunocompetent patients, since immunosuppression is a favorable background for the development of severe forms of tuberculosis. The most severe forms of tuberculosis in HIV infection include lesions of the central nervous system (CNS). This review is aimed to briefly summarize the studies of HIV-associated tuberculosis with CNS involvement, its clinical manifes-tations, complications, including those associated with the immune reconstitution inflammatory syndrome, dif-ferential diagnostics with other HIV-associated lesions of the central nervous system, methods of laboratory diag-nostics, and specifics of tuberculosis treatment in cases of high viral load. The study of possible influence of the genotype of the infecting Mycobacterium tuberculosis strains on the course and outcome of the disease is an important area for future research.

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Central Nervous System (CNS) Viral Seeding by Mature Monocytes and Potential Therapies To Reduce CNS Viral Reservoirs in the cART Era

mBio ◽

10.1128/mbio.03633-20 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Rosiris León-Rivera ◽

Mike Veenstra ◽

Maribel Donoso ◽

Elizabeth Tell ◽

Eliseo A. Eugenin ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mononuclear Cells ◽

Viral Reservoir ◽

People Living With Hiv ◽

Viral Reservoirs ◽

Peripheral Blood Mononuclear ◽

Active Viral Replication ◽

The Central Nervous System

ABSTRACT The human immunodeficiency virus (HIV) enters the central nervous system (CNS) within a few days after primary infection, establishing viral reservoirs that persist even with combined antiretroviral therapy (cART). We show that monocytes from people living with HIV (PLWH) on suppressive cART harboring integrated HIV, viral mRNA, and/or viral proteins preferentially transmigrate across the blood-brain barrier (BBB) to CCL2 and are significantly enriched post-transmigration, and even more highly enriched posttransmigration than T cells with similar properties. Using HIV-infected ART-treated mature monocytes cultured in vitro, we recapitulate these findings and demonstrate that HIV+ CD14+ CD16+ ART-treated monocytes also preferentially transmigrate. Cenicriviroc and anti-JAM-A and anti-ALCAM antibodies significantly and preferentially reduce/block transmigration of HIV+ CD14+ CD16+ ART-treated monocytes. These findings highlight the importance of monocytes in CNS HIV reservoirs and suggest targets to eliminate their formation and reseeding. IMPORTANCE We characterized mechanisms of CNS viral reservoir establishment/replenishment using peripheral blood mononuclear cells (PBMC) of PLWH on cART and propose therapeutic targets to reduce/block selective entry of cells harboring HIV (HIV+) into the CNS. Using DNA/RNAscope, we show that CD14+ CD16+ monocytes with integrated HIV, transcriptionally active, and/or with active viral replication from PBMC of PLWH prescribed cART and virally suppressed, selectively transmigrate across a human BBB model. This is the first study to our knowledge demonstrating that monocytes from PLWH with HIV disease for approximately 22 years and with long-term documented suppression can still carry virus into the CNS that has potential to be reactivated and infectious. This selective entry into the CNS—and likely other tissues—indicates a mechanism of reservoir formation/reseeding in the cART era. Using blocking studies, we propose CCR2, JAM-A, and ALCAM as targets on HIV+ CD14+ CD16+ monocytes to reduce and/or prevent CNS reservoir replenishment and to treat HAND and other HIV-associated comorbidities.

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