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HIV latency reactivation

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https://www.readbyqxmd.com/read/27898737/transcriptomic-analysis-implicates-the-p53-signaling-pathway-in-the-establishment-of-hiv-1-latency-in-central-memory-cd4-t-cells-in-an-in-vitro-model
#1
Cory H White, Bastiaan Moesker, Nadejda Beliakova-Bethell, Laura J Martins, Celsa A Spina, David M Margolis, Douglas D Richman, Vicente Planelles, Alberto Bosque, Christopher H Woelk
The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27898590/reactivation-of-simian-immunodeficiency-virus-reservoirs-in-the-brain-of-virally-suppressed-macaques
#2
Lucio Gama, Celina M Abreu, Erin N Shirk, Sarah L Price, Ming Li, Greg M Laird, Kelly A Metcalf Pate, Stephen W Wietgrefe, Shelby L O'Connor, Luiz Pianowski, Ashley T Haase, Carine Van Lint, Robert F Siliciano, Janice E Clements
OBJECTIVE: Resting CD4 T cells have been recognized as the major cell reservoir of latent HIV-1 during antiretroviral therapy (ART). Using an simian immunodeficiency virus (SIV)/macaque model for AIDS and HIV-related neurocognitive disorders we assessed the contribution of the brain to viral latency and reactivation. DESIGN: Pigtailed macaques were dual inoculated with SIVDeltaB670 and SIV17E-Fr and treated with an efficacious central nervous system-penetrant ART...
January 2, 2017: AIDS
https://www.readbyqxmd.com/read/27889530/identification-of-proximal-biomarkers-of-pkc-agonism-and-evaluation-of-their-role-in-hiv-reactivation
#3
Sai Vikram Vemula, Jill W Maxwell, Alexey Nefedov, Bang-Lin Wan, Justin Steve, William Newhard, Rosa I Sanchez, David Tellers, Richard J Barnard, Wade Blair, Daria Hazuda, Andrea L Webber, Bonnie J Howell
DESIGN: The HIV latent CD4(+) T cell reservoir is broadly recognized as a barrier to HIV cure. Induction of HIV expression using protein kinase C (PKC) agonists is one approach under investigation for reactivation of latently infected CD4(+) T cells (Beans et al., 2013; Abreu et al., 2014; Jiang et al., 2014; Jiang and Dandekar, 2015). We proposed that an increased understanding of the molecular mechanisms of action of PKC agonists was necessary to inform on biological signaling and pharmacodynamic biomarkers...
November 23, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27870832/position-effects-influence-hiv-latency-reversal
#4
Heng-Chang Chen, Javier P Martinez, Eduard Zorita, Andreas Meyerhans, Guillaume J Filion
The main obstacle to curing HIV is the presence of latent proviruses in the bodies of infected patients. The partial success of reactivation therapies suggests that the genomic context of integrated proviruses can interfere with treatment. Here we developed a method called Barcoded HIV ensembles (B-HIVE) to map the chromosomal locations of thousands of individual proviruses while tracking their transcriptional activities in an infected cell population. B-HIVE revealed that, in Jurkat cells, the expression of HIV is strongest close to endogenous enhancers...
November 21, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27837106/cutting-edge-t-regulatory-cell-depletion-reactivates-latent-simian-immunodeficiency-virus-siv-in-controller-macaques-while-boosting-siv-specific-t-lymphocytes
#5
Tianyu He, Egidio Brocca-Cofano, Benjamin B Policicchio, Ranjit Sivanandham, Rajeev Gautam, Kevin D Raehtz, Cuiling Xu, Ivona Pandrea, Cristian Apetrei
T regulatory cells (Tregs) are critical in shaping the latent HIV/SIV reservoir, as they are preferentially infected, reverse CD4(+) T cell activation status, and suppress CTL responses. To reactivate latent virus and boost cell-mediated immune responses, we performed in vivo Treg depletion with Ontak (denileukin diftitox) in two SIVsab-infected controller macaques. Ontak induced significant (>75%) Treg depletion and major CD4(+) T cell activation, and only minimally depleted CD8(+) T cells. The overall ability of Tregs to control immune responses was significantly impaired despite their incomplete depletion, resulting in both reactivation of latent virus (virus rebound to 10(3) viral RNA copies/ml plasma in the absence of antiretroviral therapy) and a significant boost of SIV-specific CD8(+) T cell frequency, with rapid clearance of reactivated virus...
December 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27799305/heat-shock-protein-90-facilitates-latent-hiv-reactivation-through-maintaining-the-function-of-positive-transcriptional-elongation-factor-b-p-tefb-under-proteasome-inhibition
#6
Xiao-Yan Pan, Wei Zhao, Chun-Yan Wang, Jian Lin, Xiao-Yun Zeng, Ru-Xia Ren, Keng Wang, Tian-Rong Xun, Yechiel Shai, Shu-Wen Liu
The persistence of HIV in resting memory CD4+ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex...
October 31, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27795436/naf1-regulates-hiv-1-latency-by-suppressing-viral-promoter-driven-gene-expression-in-primary-cd4-t-cells
#7
Chuan Li, Hai-Bo Wang, Wen-Dong Kuang, Xiao-Xin Ren, Shu-Ting Song, Huan-Zhang Zhu, Qiang Li, Li-Ran Xu, Hui-Jun Guo, Li Wu, Jian-Hua Wang
: HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating the LTR activity contribute to HIV-1 latency and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleo-cytoplasmic shuttling protein and regulates multiple cellular signal pathways and HIV-1 production. We have recently reported that the nucleus-located Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to the accumulated Gag production...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27795414/identification-of-novel-kshv-orf50-transcripts-discovery-of-new-rta-isoforms-with-variable-transactivation-potential
#8
Brian S Wakeman, Yoshihiro Izumiya, Samuel H Speck
: Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that has been associated with primary effusion lymphoma, multicentric Castleman's disease, as well as its namesake Kaposi's sarcoma. As a gammaherpesvirus, KSHV is able to acutely replicate, enter latency, and reactivate from this latent state. A key protein involved in both acute replication and reactivation from latency is the replication and transcriptional activator (RTA) encoded by the gene Orf50. RTA is a known transactivator of multiple viral genes allowing for it to control the switch between latency and virus replication...
October 19, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27769267/activation-of-hiv-1-expression-in-latently-infected-cd4-t-cells-by-the-small-molecule-pkc412
#9
Zhujun Ao, Rong Zhu, Xiaoli Tan, Lisa Liu, Liyu Chen, Shuiping Liu, XiaoJian Yao
BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells...
October 21, 2016: Virology Journal
https://www.readbyqxmd.com/read/27757411/ongoing-clinical-trials-of-human-immunodeficiency-virus-latency-reversing-and-immunomodulatory-agents
#10
Héloïse M Delagrèverie, Constance Delaugerre, Sharon R Lewin, Steven G Deeks, Jonathan Z Li
In chronic human immunodeficiency virus (HIV)-1 infection, long-lived latently infected cells are the major barrier to virus eradication and functional cure. Several therapeutic strategies to perturb, eliminate, and/or control this reservoir are now being pursued in the clinic. These strategies include latency reversal agents (LRAs) designed to reactivate HIV-1 ribonucleic acid transcription and virus production and a variety of immune-modifying drugs designed to reverse latency, block homeostatic proliferation, and replenish the viral reservoir, eliminate virus-producing cells, and/or control HIV replication after cessation of antiretroviral therapy...
October 2016: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/27755105/reactivation-capacity-by-latency-reversing-agents-ex-vivo-correlates-with-the-size-of-the-hiv-1-reservoir
#11
Gilles Darcis, Sophie Bouchat, Anna Kula, Benoit Van Driessche, Nadège Delacourt, Caroline Vanhulle, Véronique Avettand-Fenoel, Stéphane De Wit, Olivier Rohr, Christine Rouzioux, Carine Van Lint
OBJECTIVE: HIV-1 reservoirs are the major hurdle to virus clearance in cART-treated patients. An approach to eradicating HIV-1 involves reversing latency in cART-treated patients in order to make latent cells visible to the host immune system. Stimulation of patient cell cultures with LRAs ex vivo results in heterogeneous responses among HIV-infected patients. Determinants of this heterogeneity are unknown and consequently, important to determine. DESIGN AND METHODS: Here, we grouped and retrospectively analyzed the data from our two recent HIV-1 reactivation studies to investigate the role of the HIV-1 reservoir size in the reactivation capacity by LRAs in ex vivo cultures of CD8-depleted PBMCs isolated from 54 cART-treated patients and of resting CD4 T cells isolated from 30 cART-treated patients...
October 14, 2016: AIDS
https://www.readbyqxmd.com/read/27750386/the-impact-of-ebv-and-hiv-infection-on-the-microenvironmental-niche-underlying-hodgkin-lymphoma-pathogenesis
#12
Antonino Carbone, Annunziata Gloghini, Arnaldo Caruso, Paolo De Paoli, Riccardo Dolcetti
The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumour cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27746784/targeting-the-brain-reservoirs-toward-an-hiv-cure
#13
Céline Marban, Faezeh Forouzanfar, Amina Ait-Ammar, Faiza Fahmi, Hala El Mekdad, Fadoua Daouad, Olivier Rohr, Christian Schwartz
One of the top research priorities of the international AIDS society by the action "Towards an HIV Cure" is the purge or the decrease of the pool of all latently infected cells. This strategy is based on reactivation of latently reservoirs (the shock) followed by an intensifying combination antiretroviral therapy (cART) to kill them (the kill). The central nervous system (CNS) has potential latently infected cells, i.e., perivascular macrophages, microglial cells, and astrocytes that will need to be eliminated...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27709447/current-views-on-hiv-1-latency-persistence-and-cure
#14
Zora Melkova, Prakash Shankaran, Michaela Madlenakova, Josef Bodor
HIV-1 infection cannot be cured as it persists in latently infected cells that are targeted neither by the immune system nor by available therapeutic approaches. Consequently, a lifelong therapy suppressing only the actively replicating virus is necessary. The latent reservoir has been defined and characterized in various experimental models and in human patients, allowing research and development of approaches targeting individual steps critical for HIV-1 latency establishment, maintenance, and reactivation...
October 5, 2016: Folia Microbiologica
https://www.readbyqxmd.com/read/27697031/reactivation-of-latent-hiv-1-in-latently-infected-cells-by-coumarin-compounds-hymecromone-and-scoparone
#15
Xian Li, Hanxian Zeng, Pengfei Wang, Lu Lin, Lin Liu, Panpan Lu, Huanzhang Zhu
BACKGROUND: Current antiretroviral treatment (ART) cannot cure HIV-1 infection due to the presence of latent viral reservoirs. The "shock and kill" strategy is a promising approach to eliminate the viral reservoir. However, there are various limits existing in current latency-reversing agents, searching for new activators are urgently needed. OBJECTIVE: The present study aimed at investigating the ability of hymecromone and scoparone for activating HIV-1 from latent reservoirs...
October 3, 2016: Current HIV Research
https://www.readbyqxmd.com/read/27662631/differences-in-activation-of-hiv-1-replication-by-superinfection-with-hiv-1-and-hiv-2-in-u1-cells
#16
Xue Wang, Bing Sun, Christelle Mbondji, Santanu Biswas, Jiangqin Zhao, Indira Hewlett
Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir that serve as a viral source for the infection of CD4 T cells. The relationship between HIV-1 latent infection and superinfection in macrophages has not been well studied. Using susceptible U1 cells chronically infected with HIV-1, we studied the effects of HIV superinfection on latency and differences in superinfection with HIV-1 and HIV-2 in macrophages. We found that HIV-1 (MN) superinfection displayed increased HIV-1 replication in a time-dependent manner; while cells infected with HIV-2 (Rod) initially showed increased HIV-1 replication, followed by a decrease in HIV-1 RNA production...
September 23, 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27662554/reactivation-of-siv-reservoirs-in-the-brain-of-virally-suppressed-macaques
#17
Lucio Gama, Celina M Abreu, Erin N Shirk, Sarah L Price, Ming Li, Greg M Laird, Kelly A Metcalf Pate, Stephen W Wietgrefe, Shelby L O'connor, Luiz Pianowski, Ashley T Haase, Carine Van Lint, Robert F Siliciano, Janice E Clements, Dummy Authors
OBJECTIVE: Resting CD4+ T cells have been recognized as the major cell reservoir of latent HIV-1 during antiretroviral therapy (ART). Using an SIV/macaque model for AIDS and HIV-related neurocognitive disorders we assessed the contribution of the brain to viral latency and reactivation. DESIGN: Pigtailed macaques were dual inoculated with SIVDeltaB670 and SIV17E-Fr and treated with an efficacious CNS-penetrant ART. After 500 days of viral suppression animals were treated with two cycles of latency reversing agents (LRAs) and increases in viral transcripts were examined...
September 20, 2016: AIDS
https://www.readbyqxmd.com/read/27610026/cytomegalovirus-related-fatal-duodenal-diverticular-bleeding-case-report-and-literature-review
#18
Jasbir Makker, Bharat Bajantri, Sailaja Sakam, Sridhar Chilimuri
Involvement of gastrointestinal tract by cytomegalovirus (CMV) is common. CMV infections mainly run their course without any clinical signs in immunocompetent hosts. In contrast, CMV can cause severe infections with serious consequences in a immunocompromised state typically associated with organ transplants, highly immunosuppressive cancer chemotherapy, advanced HIV infection or treatment with corticosteroids. The incidence and severity of these manifestations of CMV is directly proportional with the degree of cellular immune dysfunction, i...
August 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27572460/roles-of-micrornas-in-hiv-1-replication-and-latency
#19
Binlian Sun, Rongge Yang, Massimo Mallardo
MicroRNAs (miRNAs) are non-coding RNA molecules, with sequence length of 19-24 nucleotides, which can induce mRNA degradation and regulate protein translation repression. Recently plenty of reports showed that miRNAs increase or decrease in the serum (circulating miRNAs) and in PBMC of Human immunodeficiency virus type I (HIV-1) infected individuals to affect the replication of HIV-1 through regulating HIV-1 proteins or HIV-1 replication related host factors. Many of miRNAs can suppress HIV-1 replication, but do not affect the integrated viral DNA...
August 29, 2016: MicroRNA
https://www.readbyqxmd.com/read/27561082/correction-hiv-reactivation-from-latency-after-treatment-interruption-occurs-on-average-every-5-8-days-implications-for-hiv-remission
#20
Mykola Pinkevych, Deborah Cromer, Martin Tolstrup, Andrew J Grimm, David A Cooper, Sharon R Lewin, Ole S Søgaard, Thomas A Rasmussen, Stephen J Kent, Anthony D Kelleher, Miles P Davenport
[This corrects the article DOI: 10.1371/journal.ppat.1005000.][This corrects the article DOI: 10.1371/journal.ppat.1005740.][This corrects the article DOI: 10.1371/journal.ppat.1005679.].
August 2016: PLoS Pathogens
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