HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

Romani, Bizhan; Jamil, Razieh Kamali; Hamidi-Fard, Mojtaba; Rahimi, Pooneh; Momen, Seyed Bahman; Aghasadeghi, Mohammad Reza; Allahbakhshi, Elham

doi:10.1038/srep31924

Cited by 33 publications

(24 citation statements)

References 64 publications

(91 reference statements)

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“…It is also reported that inhibition of HDAC3 could induce cell autophagy in human glioma cells [ 29 ], and apoptosis in cholangiocarcinoma [ 30 ]. Besides their utilization as targets in cancer therapy, class I HDACs have gained considerable attention as targets in the search for treatments for degenerative neurological diseases, such as Alzheimer’s and Huntington’s disease [ 20 , 31 , 32 , 33 , 34 ], chronic inflammatory diseases, like asthma and COPD [ 35 , 36 , 37 , 38 ], viral infections [ 39 ], especially for human immunodeficiency virus (HIV) [ 40 , 41 , 42 ], and diabetes [ 22 , 43 , 44 , 45 ]. HDAC3, in particular, is an interesting target in Alzheimer’s disease [ 31 , 46 ], since it is reported that HDAC3 plays an important role in maintaining long-term memory for object location [ 47 ].…”

Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.

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Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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“…In mouse models exposed to vpr via transgenic expression, direct injections, or ALZET osmotic pumps, Balasubramanyam et al and Agarwal et al further demonstrated that vpr impairs adipocyte growth and function, increases adipose inflammation, dysregulates systemic lipid metabolism, and promotes fatty liver disease [28, 33, 34]. Importantly for HIV-infected quiescent CD4 T cells in different tissue reservoirs, circulating vpr can also reactivate latent provirus [89, 90]. Adipocytes exposed to tat and nef in vitro also result in suppression of PPARγ function and adipogenesis, as well as the upregulation of inflammatory cytokines and impairment of glucose uptake [29, 31, 32].…”

Section: Composition and Functions Of Immune Cells In Adipose Tissue mentioning

confidence: 99%

HIV Persistence in Adipose Tissue Reservoirs

Couturier

Lewis

2018

Curr HIV/AIDS Rep

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Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

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“…Vpr plays an important role in the pathogenesis of SIV in macaques (reviewed in [168]). It induces viral reactivation by promoting the degradation of histone deacetylase 1 and 3 and inducing the production of IL-6 [169, 170]. It promotes activation of HIV promoter by inducing the expression of hypoxia-inducible factor 1-α through increased production of ROS [171, 172].…”

Section: Role Of Hiv-1 Proteins In Neurotoxicitymentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

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HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

Cited by 33 publications

References 64 publications

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

HIV Persistence in Adipose Tissue Reservoirs

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

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