HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

Graci, Jason D.; Colacino, Joseph M.; Peltz, Stuart W.; Dougherty, Joseph P.; Gu, Zhengxian

doi:10.1177/095632020901900501

Cited by 5 publications

(10 citation statements)

References 113 publications

(161 reference statements)

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“…As the HIV provirus can integrate into many different chromosomal locations in the cell it is tempting to explain viral latency (vs. transcriptional activity) as integration into repressed heterochromatin. While this is at least in part true, it is not the whole story (for reviews on HIV viral latency, see (Han et al 2007; Coiras et al 2009; Graci et al 2009)).…”

Section: The Life Cycle Of Hivmentioning

confidence: 99%

A perspective of the dynamic structure of the nucleus explored at the single-molecule level

2010

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Cellular life can be described as a dynamic equilibrium of a highly complex network of interacting molecules. For this reason, it is no longer sufficient to “only” know the identity of the participants in a cellular process, but questions such as where, when, and for how long also have to be addressed to understand the mechanism being investigated. Additionally, ensemble measurements may not sufficiently describe individual steps of molecular mobility, spatial-temporal resolution, kinetic parameters, and geographical mapping. It is vital to investigate where individual steps exactly occur to enhance our understanding of the living cell. The nucleus, home too many highly complex multi-order processes, such as replication, transcription, splicing, etc., provides a complicated, heterogeneous landscape. Its dynamics were studied to a new level of detail by fluorescence correlation spectroscopy (FCS). Single-molecule tracking, while still in its infancy in cell biology, is becoming a more and more attractive method to deduce key elements of this organelle. Here we discuss the potential of tracking single RNAs and proteins in the nucleus. Their dynamics, localization, and interaction rates will be vital to our understanding of cellular life. To demonstrate this, we provide a review of the HIV life cycle, which is an extremely elegant balance of nuclear and cytoplasmic functions and provides an opportunity to study mechanisms deeply integrated within the structure of the nucleus. In summary, we aim to present a specific, dynamic view of nuclear cellular life based on single molecule and FCS data and provide a prospective for the future.

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Section: The Life Cycle Of Hivmentioning

confidence: 99%

A perspective of the dynamic structure of the nucleus explored at the single-molecule level

2010

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“…The primary HIV reservoirs tend to be latent CD4 + T cells, monocyte‐macrophages, and hematopoietic cells. Despite the presence of only a limited number of latent cells, the decay rate is quite slow, which is why HAART cannot completely eradicate the virus …”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation

Kuai

Qiao

et al. 2018

Journal of Medical Virology

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Highly active antiretroviral therapy can reduce the human immunodeficiency virus (HIV) viral load in the plasma to undetectable levels. However, because of the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor recently approved for cancer treatment by the China Food and Drug Administration, to reactivate latent HIV-1 via histone acetylation. Viral reactivities of chidamide were accessed in 2 latent HIV pseudotype virus cell reporter systems (J-Lat Tat-green fluorescent protein clone A72 and TZM-bl), a latently infected full-length HIV virus cell system (U1/HIV), and resting CD4 T cells from 9 HIV-infected patients under highly active antiretroviral therapy with undetectable viral load. Chidamide was able to increase HIV expression in each cell line, as evidenced by green fluorescent protein, luciferase activity, and p24, as well as to reactivate latent HIV-1 in primary CD4 T cells of HIV-infected patients. Histone acetylation adjacent to the HIV promoter in A72 cells was determined by chromatin immunoprecipitation. Chidamide was able to increase histone H3 and H4 acetylation at the HIV promoter. In brief, chidamide induced the reactivation of latent HIV in pseudotype virus reporter cells, latently infected cells, and primary CD4 T cells, making this compound an attractive option for future clinical trials.

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“…The mechanisms underlying HIV-1 latency are not fully characterized, and evidence suggests that multiple processes maintain the latent provirus [18–20]. Factors that contribute to proviral latency include: 1) a lack of expression of appropriate transcription factors in resting cells [21,22]; 2) silencing of viral gene expression due to chromosome structure or epigenetic modifications at the site of provirus integration [23–26]; 3) premature transcriptional termination due to insufficient levels of Tat and associated host factors [27–29]; 4) ineffective transport of viral RNAs encoding the late viral proteins, such as Gag, Pol and Env (for review see [19]); 5) transcriptional interference [30]; and 6) silencing of viral gene expression via microRNAs [31,32].…”

Section: Introductionmentioning

confidence: 99%

Identification of benzazole compounds that induce HIV-1 transcription

et al. 2017

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Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed “shock and kill”. This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents.

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HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

Cited by 5 publications

References 113 publications

A perspective of the dynamic structure of the nucleus explored at the single-molecule level

A perspective of the dynamic structure of the nucleus explored at the single-molecule level

Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation

Identification of benzazole compounds that induce HIV-1 transcription

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