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Latent hiv reservoir

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
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
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
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
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
Xia Wang, Sanyi Tang, Xinyu Song, Libin Rong
HIV can infect cells via virus-to-cell infection or cell-to-cell viral transmission. These two infection modes may occur in a synergistic way and facilitate viral spread within an infected individual. In this paper, we developed an HIV latent infection model including both modes of transmission and time delays between viral entry and integration or viral production. We analysed the model by defining the basic reproductive number, showing the existence, positivity and boundedness of the solution, and proving the local and global stability of the infection-free and infected steady states...
October 12, 2016: Journal of Biological Dynamics
Rahul Sampath, Nathan W Cummins, Andrew D Badley
HIV cure is now the focus of intense research after Timothy Ray Brown (the Berlin patient) set the precedent of being the first and only person cured. A major barrier to achieving this goal on a meaningful scale is an elimination of the latent reservoir, which is thought to comprise CD4-positive cells that harbor integrated, replication-competent HIV provirus. These cells do not express viral proteins, are indistinguishable from uninfected CD4 cells, and are thought to be responsible for HIV viral rebound-that occurs within weeks of combination anti retroviral therapy (cART) interruption...
2016: Journal of Cell Death
K F Gurski, K A Hoffman
In 1992, Watts and May introduced a simple dynamical systems model of the spread of HIV based on disease transmission per partnership including the length of partnership duration. This model allowed for the treatment of concurrent partnerships, although it was hampered by the assumption of an important latent phase which generated a non-autonomous system. Subsequent models including concurrency have been based on networks, Monte Carlo, and stochastic simulations which lose a qualitative understanding of the effects of concurrency...
October 3, 2016: Mathematical Biosciences
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
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
Sook-Kyung Lee, Shuntai Zhou, Pedro L Baldoni, Ean Spielvogel, Nancie M Archin, Michael G Hudgens, David M Margolis, Ronald Swanstrom
BACKGROUND: In this study, we measured the latent HIV-1 reservoir harboring replication-competent HIV-1 in resting CD4+ T cells in participants on highly active antiretroviral therapy (HAART), quantitating the frequency of latent infection through the use of a Primer ID-based Ultra Deep Sequencing Assay (UDSA), in comparison to the readout of the quantitative viral outgrowth assay (QVOA). METHODS: Viral RNA derived from culture wells of QVOA that scored as HIV-1 p24 capsid (CA) antigen-positive were tagged with a specific barcode during cDNA synthesis, and the sequences within the V1-V3 region of the HIV-1 env gene were analyzed for diversity using the Primer ID-based paired-end MiSeq platform...
September 27, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Hoyong Lim, Kyung-Chang Kim, Junseock Son, Younghyun Shin, Cheol-Hee Yoon, Chun Kang, Byeong-Sun Choi
HIV-1 reservoirs remain a major barrier to HIV-1 eradication. Although combination antiretroviral therapy (cART) can successfully reduce viral replication, it cannot reactivate HIV-1 provirus in this reservoir. Therefore, HIV-1 provirus reactivation strategies by cell activation or epigenetic modification are proposed for the eradication of HIV-1 reservoirs. Although treatment with the protein kinase A (PKA) activator cyclic AMP (cAMP) or epigenetic modifying agents such as histone deacetylase inhibitors (HDACi) alone can induce HIV-1 reactivation in latently infected cells, the synergism of these agents has not been fully evaluated...
September 24, 2016: Virus Research
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
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
Steffen Leth, Mariane H Schleimann, Sara K Nissen, Jesper F Højen, Rikke Olesen, Mette E Graversen, Sofie Jørgensen, Anne Sofie Kjær, Paul W Denton, Alejandra Mørk, Maja A Sommerfelt, Kim Krogsgaard, Lars Østergaard, Thomas A Rasmussen, Martin Tolstrup, Ole Schmeltz Søgaard
BACKGROUND: Immune priming before reversal of latency might be a component of a functional HIV cure. To assess this concept, we assessed if therapeutic HIV immunisation followed by latency reversal would affect measures of viral transcription, plasma viraemia, and reservoir size in patients with HIV on suppressive antiretroviral therapy. METHODS: In this single-arm, phase 1B/2A trial, we recruited adults treated at the Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark (aged ≥18 years) with successfully treated HIV-1 with plasma RNA loads of less than 50 copies per mL for the previous year and CD4 counts of at least 500 cells per μL...
October 2016: Lancet HIV
Zhou Qihui, Zhu Biao
Latent reservoir (LR) of HIV is the cells (such as CD4(+)T cell) where HIV is able to hide. These cellular reservoirs are located throughout the body, including the spleen, lymph nodes, gastrointestinal lymphoid tissues, and become the major obstacle to cure HIV infection. To truly cure patients, a new strategy "shock and kill" was put forward by scientists, which is to shock HIV-infected cells out of hidden reservoirs in the body and then kill them. Quantitatively evaluating the size of long-lived LR is essential to this strategy...
May 25, 2016: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Benjamin B Policicchio, Cuiling Xu, Egidio Brocca-Cofano, Kevin D Raehtz, Tianyu He, Dongzhu Ma, Hui Li, Ranjit Sivanandham, George S Haret-Richter, Tammy Dunsmore, Anita Trichel, John W Mellors, Beatrice H Hahn, George M Shaw, Ruy M Ribeiro, Ivona Pandrea, Cristian Apetrei
Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms...
September 2016: PLoS Pathogens
Marilia Rita Pinzone, Erin Graf, Lindsay Lynch, Brigit McLaughlin, Frederick M Hecht, Mark Connors, Stephen A Migueles, Wei-Ting Hwang, Giuseppe Nunnari, Una O'Doherty
: The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both Elite Controllers (ECs, n=8) and Non-Controllers (NCs, n=6) before ART, whereas integration remained stable in patients on ART (n=4). The median annual fold-change was higher in NCs compared to ECs and negatively correlated with CD4/CD8 T-cell ratio...
September 14, 2016: Journal of Virology
Gero Hütter
HIV-1 can persist in a latent form in resting memory CD4+ cells and macrophages carrying an integrated copy of the HIV genome. Because of the presence of these stable reservoir cells, eradication by antiretroviral therapy is unlikely and in order to achieve eradication, alternative treatment options are required. Stem cell transplantation has been considered previously to effect the clinical course of HIV-infection but in practice eradication or virus control was not achievable. However, modifications of stem cell transplantation using natural or artificial resistant cell sources, combination with new techniques of gene editing or generating cytotoxic anti HIV effector cells have stimulated this field of HIV cell therapy substantially...
2016: AIDS Research and Therapy
Ajeet Kaushik, Rahul Dev Jayant, Madhavan Nair
This viewpoint is a global call to promote fundamental and applied research aiming toward designing smart nanocarriers of desired properties, novel noninvasive strategies to open the blood-brain barrier (BBB), delivery/release of single/multiple therapeutic agents across the BBB to eradicate neurohuman immunodeficiency virus (HIV), strategies for on-demand site-specific release of antiretroviral therapy, developing novel nanoformulations capable to recognize and eradicate latently infected HIV reservoirs, and developing novel smart analytical diagnostic tools to detect and monitor HIV infection...
2016: International Journal of Nanomedicine
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