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Latent hiv reservoir

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https://www.readbyqxmd.com/read/28732051/cd4-is-expressed-on-a-heterogeneous-subset-of-hematopoietic-progenitors-which-persistently-harbor-cxcr4-and-ccr5-tropic-hiv-proviral-genomes-in-vivo
#1
Nadia T Sebastian, Thomas D Zaikos, Valeri Terry, Frances Taschuk, Lucy A McNamara, Adewunmi Onafuwa-Nuga, Ryan Yucha, Robert A J Signer, James Riddell, Dale Bixby, Norman Markowitz, Sean J Morrison, Kathleen L Collins
Latent HIV infection of long-lived cells is a barrier to viral clearance. Hematopoietic stem and progenitor cells are a heterogeneous population of cells, some of which are long-lived. CXCR4-tropic HIVs infect a broad range of HSPC subtypes, including hematopoietic stem cells, which are multi-potent and long-lived. However, CCR5-tropic HIV infection is limited to more differentiated progenitor cells with life spans that are less well understood. Consistent with emerging data that restricted progenitor cells can be long-lived, we detected persistent HIV in restricted HSPC populations from optimally treated people...
July 21, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28729655/a-crispr-cas9-guidance-rna-screen-platform-for-hiv-provirus-disruption-and-hiv-aids-gene-therapy-in-astrocytes
#2
Zaohua Huang, Madahavan Nair
HIV/AIDS remains a major health threat despite significant advances in the prevention and treatment of HIV infection. The major reason is the inability of existing treatments to eradicate the multiple HIV reservoirs in the human body, including astrocytes in the human brain. CRISPR/Cas9 system is an emerging gene-editing technique with the potential to eliminate or disrupt HIV provirus in HIV reservoir cells, which may lead to a complete cure of HIV/AIDS. The key components of CRISPR/Cas9 are guide RNAs (gRNAs) which determine specific sequence targeting of DNAs...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28715973/the-molecular-basis-for-human-immunodeficiency-virus-latency
#3
Uri Mbonye, Jonathan Karn
Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4(+) T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment...
July 17, 2017: Annual Review of Virology
https://www.readbyqxmd.com/read/28692305/fight-fire-with-fire-gene-therapy-strategies-to-cure-hiv
#4
Jon Huyghe, Sips Magdalena, Linos Vandekerckhove
Human Immunodeficiency Virus (HIV) to date remains one of the most notorious viruses mankind has ever faced. Despite enormous investments in HIV research for more than 30 years an effective cure for HIV has been elusive. Areas covered: Combination antiretroviral therapy (cART) suppresses active viral replication, but is not able to eliminate the virus completely due to stable integration of HIV inside the host genome of infected cells and the establishment of a latent reservoir, that is insensitive to cART...
July 14, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/28689087/the-histone-deacetylase-inhibitor-saha-simultaneously-reactivates-hiv-1-from-latency-and-up-regulates-nkg2d-ligands-sensitizing-for-natural-killer-cell-cytotoxicity
#5
Maria Giovanna Desimio, Erica Giuliani, Margherita Doria
In pilot HIV-1 eradication studies, patients' immune responses were ineffective at killing viral reservoirs reactivated through latency reversing agents (LRAs) like suberoylanilide hydroxamic acid (SAHA). We hypothesized that T cells harboring reactivated HIV-1 express MIC and ULBP ligands for the activating NKG2D receptor of natural killer (NK) cells. Here, we demonstrated that MICA/B and ULBP2 are induced by SAHA on primary T cells harboring reactivated virus. Using latently HIV-1-infected J-Lat 6.3/8.4/9...
July 6, 2017: Virology
https://www.readbyqxmd.com/read/28687465/on-the-way-to-find-a-cure-purging-latent-hiv-1-reservoirs
#6
REVIEW
Christian Schwartz, Sophie Bouchat, Céline Marban, Virginie Gautier, Carine Van Lint, Olivier Rohr, Valentin Le Douce
Introduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs. Evidence is now accumulating that purging the HIV-1 reservoir might lead to a cure or a remission. The most studied strategy is the so called "shock and kill" therapy. This strategy is based on reactivation of dormant viruses from the latently-infected reservoirs (the shock) followed by the eradication of the reservoirs (the kill)...
July 4, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28673572/elimination-of-cancer-stem-cells-and-reactivation-of-latent-hiv-1-via-ampk-activation-common-mechanism-of-action-linking-inhibition-of-tumorigenesis-and-the-potential-eradication-of-hiv-1
#7
Jahahreeh Finley
Although promising treatments are currently in development to slow disease progression and increase patient survival, cancer remains the second leading cause of death in the United States. Cancer treatment modalities commonly include chemoradiation and therapies that target components of aberrantly activated signaling pathways. However, treatment resistance is a common occurrence and recent evidence indicates that the existence of cancer stem cells (CSCs) may underlie the limited efficacy and inability of current treatments to effectuate a cure...
July 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28658263/identification-of-benzazole-compounds-that-induce-hiv-1-transcription
#8
Jason D Graci, Daniel Michaels, Guangming Chen, Gillian M Schiralli Lester, Sarah Nodder, Marla Weetall, Gary M Karp, Zhengxian Gu, Joseph M Colacino, Andrew J Henderson
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"...
2017: PloS One
https://www.readbyqxmd.com/read/28656010/chromatin-regulation-and-the-histone-code-in-hiv-latency%C3%A2
#9
REVIEW
Anne-Marie W Turner, David M Margolis
The formation of a latent reservoir of Human Immunodeficiency Virus (HIV) infection hidden from immune clearance remains a significant obstacle to approaches to eradicate HIV infection. Towards an understanding of the mechanisms of HIV persistence, there is a growing body of work implicating epigenetic regulation of chromatin in establishment and maintenance of this latent reservoir. Here we discuss recent advances in the field of chromatin regulation, specifically in our understanding of the histone code, and how these discoveries relate to our current knowledge of the chromatin mechanisms linked to HIV transcriptional repression and the reversal of latency...
June 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/28650822/calculating-the-expected-time-to-eradicate-hiv-1-using-a-markov-chain
#10
Narayanan Viswanath
In this study, the expected time required to eradicate HIV-1 completely was found as the conditional absorbing time in a finite state space continuous-time Markov chain model. The Markov chain has two absorbing states: one corresponds to HIV eradication and another representing the possible disaster. This method allowed us to calculate the expected eradication time by solving systems of linear equations. To overcome the challenge of huge dimension of the problem, we applied a novel stop and resume technique...
October 20, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/28641539/role-of-host-factors-on-the-regulation-of-tat-mediated-hiv-1-transcription
#11
Guillaume Mousseau, Susana T Valente
BACKGROUND: The viral transactivator Tat protein is a key modulator of HIV-1 replication, as it regulates transcriptional elongation from the integrated proviral genome. Tat recruits the human transcription elongation factor b, and other host proteins, such as the super elongation complex, to activate the cellular RNA polymerase II, normally stalled shortly after transcription initiation at the HIV promoter. By means of a complex set of interactions with host cellular factors, Tat determines the fate of viral activity within the infected cell...
June 22, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28641535/hiv-1-transcription-inhibitors-increase-the-synthesis-of-viral-non-coding-rna-that-contribute-to-latency
#12
Yao A Akpamagbo, Catherine DeMarino, Michelle L Pleet, Angela Schwab, Myosotys Rodriguez, Robert A Barclay, Gavin Sampey, Sergey Iordanskiy, Nazira El-Hage, Fatah Kashanchi
BACKGROUND: HIV-1 can be preserved in long-lived resting CD4+ T- and myeloid cells, forming a viral reservoir in tissues of the infected individuals. Infected patients primarily receive cART, which, to date, is the most efficient treatment against HIV/AIDS. However, the major problem in the eradication of HIV-1 from patients is the lack of therapeutic approaches to recognize the latent HIV-1 provirus and to eliminate latently infected cells. RESULTS: In the current review, we describe the effect of HIV-1 transcriptional inhibitors CR8#13 and F07#13 using a series of in vitro and in vivo assays...
June 22, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28639194/rnaa-induced-by-tata-box-targeting-micrornas
#13
Yijun Zhang, Hui Zhang
Recent studies reveal that some nuclear microRNAs (miRNA) and synthesized siRNAs target gene promoters to activate gene transcription (RNAa). Interestingly, our group identified a novel HIV-1-encoded miRNA, miR-H3, which targets specifically the core promoter TATA box of HIV-1 and activates viral gene expression. Depletion of miR-H3 significantly impaired the replication of HIV-1. miR-H3 mimics could activate viruses from CD4(+) T cells isolated from patients receiving suppressive highly active antiretroviral therapy, which is very intriguing for reducing HIV-1 latent reservoir...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#14
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28638104/anti-proliferative-therapy-for-hiv-cure-a-compound-interest-approach
#15
Daniel B Reeves, Elizabeth R Duke, Sean M Hughes, Martin Prlic, Florian Hladik, Joshua T Schiffer
In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4(+) T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28630490/pyroptosis-superinfection-and-the-maintenance-of-the-latent-reservoir-in-hiv-1-infection
#16
Dominik Wodarz, David N Levy
A long-lived reservoir of latently infected T cells prevents antiretroviral therapy from eliminating HIV-1 infection. Furthering our understanding of the dynamics of latency generation and maintenance is therefore vital to improve treatment outcome. Using mathematical models and experiments, we suggest that the death of latently infected cells brought about by pyroptosis, or to a lesser extent by superinfection, might be key mechanisms to account for the size and composition of the latent reservoir. Pyroptosis is a form of cell death that occurs in a resting (and thus latently infected) T cell when a productively infected cell attempts cell-to-cell transmission of virus...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28628632/increasing-procaspase-8-expression-using-repurposed-drugs-to-induce-hiv-infected-cell-death-in-ex-vivo-patient-cells
#17
Rahul Sampath, Nathan W Cummins, Sekar Natesampillai, Gary D Bren, Thomas D Chung, Jason Baker, Keith Henry, Amélie Pagliuzza, Andrew D Badley
HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell-associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8...
2017: PloS One
https://www.readbyqxmd.com/read/28628041/hiv-persistence-clonal-expansion-of-cells-in-the-latent-reservoir
#18
Kyungyoon J Kwon, Robert F Siliciano
While antiretroviral therapy (ART) can reduce HIV-1 to undetectable levels, the virus generally reappears if treatment is stopped. Resurgence of the virus is due to the reactivation of T cells harboring latent integrated provirus, and recent studies indicate that proliferation of these latently infected cells helps maintain the HIV-1 reservoir. In this issue of the JCI, Lee et al. evaluated CD4+ T cell subsets to determine whether certain populations are more likely to harbor full-length, replication-competent provirus...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28625133/recent-advances-in-targeting-the-hiv-1-tat-tar-complex
#19
Fardokht A Abulwerdi, Stuart F J Le Grice
Following seminal discoveries by Rosen and co-workers in 1985, the HIV-1 TAR has emerged as one of the most extensively studied regulatory elements of the HIV-1 genome. Located adjacent to the long terminal repeat promoter, this cis-acting motif, in conjunction with the viral Tat protein, plays a critical role in viral genomic RNA synthesis via modification of the transcription complex. As such, the Tat/TAR axis has been the subject of intense efforts aimed at developing therapeutic interventions, directed against both the protein and nucleic acid components...
June 15, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28605173/barriers-to-hiv-remission-research-in-low-and-middle-income-countries
#20
REVIEW
Theresa Rossouw, Joseph D Tucker, Gert U van Zyl, Kenly Sikwesi, Catherine Godfrey
INTRODUCTION: HIV eradication and remission research has largely taken place in high-income countries. In low- and middle-income countries (LMIC), there may be factors that have a substantial impact on the size of the latent HIV reservoir and the immunological response to infection. If a curative strategy is to be available to all HIV-infected individuals, these factors must be understood. METHODS: We use a scoping review to examine the literature on biological factors that may have an impact on HIV persistence in LMIC...
June 5, 2017: Journal of the International AIDS Society
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