HIV-1 persistence in the central nervous system: viral and host determinants during antiretroviral therapy

Balcom, EF; Roda, Weston C.; Ea, Cohen; My, Li; Power, Christopher

doi:10.1016/j.coviro.2019.06.004

Cited by 24 publications

(26 citation statements)

References 130 publications

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“…In addition, most data are obtained from post mortem tissues or small samples from biopsies or tissue donations, which provides us a small and insufficient window to observe HIV behavior in tissues (36,39,57,58). Several studies showed that lymphoid tissues (such as the spleen, thymus, and GALTs as well as compartmentalized tissues such as the brain) have viral reservoirs and viral DNA can be recovered (58)(59)(60). Currently, the most examined HIV reservoirs are different populations of lymphocytes that circulate in the blood, such as CD4 + T lymphocytes (9,61,62).…”

Section: Discussionmentioning

confidence: 99%

Role of Tunneling Nanotube–like Structures during the Early Events of HIV Infection: Novel Features of Tissue Compartmentalization and Mechanism of HIV Spread

Okafo¹,

Valdebenito²,

Donoso

et al. 2020

The Journal of Immunology

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HIV has become a chronic disease despite the effective use of antiretroviral therapy (ART). However, the mechanisms of tissue colonization, viral evolution, generation of viral reservoirs, and compartmentalization are still a matter of debate due to the challenges involved in examining early events of infection at the cellular and molecular level. Thus, there is still an urgent need to explore these areas to develop effective HIV cure strategies. In this study, we describe the early events of tissue colonization and compartmentalization as well as the role of tunneling nanotube-like structures during viral spread in the presence and absence of effective antiretroviral treatment. To examine these mechanisms, NOD/SCID IL-2 RG 2/2 humanized mice were either directly infected with HIV ADA or with low numbers of HIV ADA -infected leukocytes to limit tissue colonization in the presence and absence of TAK779, an effective CCR5 blocker of HIV entry. We identify that viral seeding in tissues occurs early in a tissue-and cell typespecific manner (24-72 h). Reduction in systemic HIV replication by TAK779 treatment did not affect tissue seeding or spreading, despite reduced systemic viral replication. Tissue-associated HIV-infected cells had different properties than cells in the circulation because the virus continues to spread in tissues in a tunneling nanotube-like structure-dependent manner, despite ART. Thus, understanding these mechanisms can provide new approaches to enhance the efficacy of existing ART and HIV infection cure strategies.

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Section: Discussionmentioning

confidence: 99%

Role of Tunneling Nanotube–like Structures during the Early Events of HIV Infection: Novel Features of Tissue Compartmentalization and Mechanism of HIV Spread

Okafo¹,

Valdebenito²,

Donoso

et al. 2020

The Journal of Immunology

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“…Despite use of ART results in effective viral suppression within the systemic circulation, the virus persists in the central nervous system (CNS), as a site of viral reservoir, due to limited ART penetrance, thereby hampering efforts to eradicate HIV. The virus enters the CNS through the blood-brain barrier (BBB) within circulating lymphocytes and macrophages or directly by migrating between microvascular endothelial cells [1,2]. After crossing the BBB, viral particles are able to infect resident cells such as microglia and macrophages thus contributing to establishing a persistent infection (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Phylogenetic analysis reveals significant compartmentalization of CNS viral populations, since sequences recovered from CSF are phylogenetically distinct from those in blood, showing that CNS may be a source of reactivated viral replication independent from that in the blood. An important unsolved question is whether virus originating in the CNS can reseed the periphery and even cause failure of systemic control in otherwise virologically suppressed individuals, contributing to the development of HIV-associated neurocognitive disorder (HAND) in the course of their life [1,2]. Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS

et al. 2021

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Non-human primates (NHPs) are the most relevant model of Acquired Immunodeficiency Syndrome (AIDS) and neuroAIDS, being of great importance in explaining the pathogenesis of HIV-induced nervous system damage. Simian Immunodeficiency Virus (SIV)/ Simian-Human Immunodeficiency Virus (SHIV)-infected monkeys have provided evidence of complex interactions between the virus and host that include host immune response, viral genetic diversity, and genetic susceptibility, which may explain virus-associated central nervous system (CNS) pathology and HIV-associated neurocognitive disorders (HAND). In this article, we review the recent progress contributions obtained using monkey models of HIV infection of the CNS, neuropathogenesis and SIV encephalitis (SIVE), with an emphasis on pharmacologic therapies and dependable markers that predict development of CNS AIDS.

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“…Despite the effectiveness of ART, HIV-1-infected cells persist and can be found in the periphery and in various organ systems throughout the body [1][2][3]. In particular, HIV-1 dissemination in the central nervous system (CNS) occurs early in infection during the acute stage, with HIV-1 RNA also detectable in the cerebrospinal fluid (CSF) during the chronic infection stage [4][5][6][7][8][9]. Regardless of adherence to ART, viral residency in the CNS establishes long-term low levels of inflammation that contribute, in part, to the development of HIV-associated neurocognitive disorders (HAND), which lead to significant burdens on diagnostics, treatment, and quality of life [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to cytotoxic effects due to direct infection with HIV-1, the CNS represents an environment where secreted viral proteins, cytokines, chemokines, and small molecules can all contribute to neurotoxicity [4,[27][28][29][30][31]. Therefore, proximity to HIV-1 infected cells can result in cell and tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

et al. 2020

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Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/β-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit β-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to β-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of β-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of β-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect β-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.

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HIV-1 persistence in the central nervous system: viral and host determinants during antiretroviral therapy

Cited by 24 publications

References 130 publications

Role of Tunneling Nanotube–like Structures during the Early Events of HIV Infection: Novel Features of Tissue Compartmentalization and Mechanism of HIV Spread

Role of Tunneling Nanotube–like Structures during the Early Events of HIV Infection: Novel Features of Tissue Compartmentalization and Mechanism of HIV Spread

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

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