Translational challenges in targeting latent HIV infection and the CNS reservoir problem

Garrido, Carolina

doi:10.1007/s13365-014-0269-z

Cited by 12 publications

(13 citation statements)

References 42 publications

(43 reference statements)

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“…For example, the invasive techniques used to evaluate the evolution of biomarkers in the CSF such as neopterin, CTIP2, TREM2, and NFL after a treatment cannot be performed too frequently (Jessen Krut et al, 2014). Non-invasive methods such as neuroimaging are therefore needed for brain evaluation (discussed in Garrido and Margolis, 2015). Comprehensive neuropsychological testing is also required to detect subclinical deficits (Haddow et al, 2013).…”

Section: Targeting the Microglial Cellsmentioning

confidence: 99%

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Wallet

Rovere

Assche

et al. 2019

Front. Cell. Infect. Microbiol.

268

252

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Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.

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Section: Targeting the Microglial Cellsmentioning

confidence: 99%

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Wallet

Rovere

Assche

et al. 2019

Front. Cell. Infect. Microbiol.

268

252

View full text Add to dashboard Cite

show abstract

“…For instance, central nervous system (CNS) is one of the anatomical sanctuaries for HIV-1 latent reservoir. CNS resident macrophages such as meningeal macrophages, perivascular macrophages, macrophages of the choroid-plexus, and microglia are derived and continuously replaced by the migration of monocytes through blood brain barrier [ 13 , 14 ]. These CNS resident macrophages are susceptible to HIV-1 infection and are largely responsible for HIV-1 associated dementia [ 15 , 16 ].…”

Section: Reviewmentioning

confidence: 99%

Epigenetic control of HIV-1 post integration latency: implications for therapy

et al. 2015

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With the development of effective combined anti-retroviral therapy (cART), there is significant reduction in deaths associated with human immunodeficiency virus type 1 (HIV-1) infection. However, the complete cure of HIV-1 infection is difficult to achieve without the elimination of latent reservoirs which exist in the infected individuals even under cART regimen. These latent reservoirs established during early infection have long life span, include resting CD4+ T cells, macrophages, central nervous system (CNS) resident macrophage/microglia, and gut-associated lymphoid tissue/macrophages, and can actively produce virus upon interruption of the cART. Several epigenetic and non-epigenetic mechanisms have been implicated in the regulation of viral latency. Epigenetic mechanisms such as histone post translational modifications (e.g., acetylation and methylation) and DNA methylation of the proviral DNA and microRNAs are involved in the establishment of HIV-1 latency. The better understanding of epigenetic mechanisms modulating HIV-1 latency could give clues for the complete eradication of these latent reservoirs. Several latency-reversing agents (LRA) have been found effective in reactivating HIV-1 reservoirs in vitro, ex vivo, and in vivo. Some of these agents target epigenetic modifications to elicit viral expression in order to kill latently infected cells through viral cytopathic effect or host immune response. These therapeutic approaches aimed at achieving a sterilizing cure (elimination of HIV-1 from the human body). In the present review, we will discuss our current understanding of HIV-1 epigenomics and how this information can be moved from the laboratory bench to the patient’s bedside.

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“…We therefore favor the hypothesis that HIV persists in the CNS due primarily to the establishment of latent HIV infections, especially in the microglial cell population, which is highly permissive for HIV infection (Cenker et al 2017 ). Curing HIV will therefore require strategies that remove, disable, or suppress all latent HIV reservoirs, including those specific to the CNS (Brew et al 2015 ; Fois and Brew 2015 ; Garrido and Margolis 2015 ).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency

et al. 2017

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Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.

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Translational challenges in targeting latent HIV infection and the CNS reservoir problem

Cited by 12 publications

References 42 publications

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Epigenetic control of HIV-1 post integration latency: implications for therapy

HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency

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