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Latent hiv reservoir

Xavier Contreras, Kader Salifou, Gabriel Sanchez, Marion Helsmoortel, Emmanuelle Beyne, Lisa Bluy, Stéphane Pelletier, Emilie Rousset, Sylvie Rouquier, Rosemary Kiernan
Expression from the HIV-1 LTR can be repressed in a small population of cells, which contributes to the latent reservoir. The factors mediating this repression have not been clearly elucidated. We have identified a network of nuclear RNA surveillance factors that act as effectors of HIV-1 silencing. RRP6, MTR4, ZCCHC8 and ZFC3H1 physically associate with the HIV-1 TAR region and repress transcriptional output and recruitment of RNAPII to the LTR. Knock-down of these factors in J-Lat cells increased the number of GFP-positive cells, with a concomitant increase in histone marks associated with transcriptional activation...
March 19, 2018: PLoS Pathogens
Ulrike C Lange, Julia K Bialek, Thomas Walther, Joachim Hauber
HIV infection is characterized by accumulation of proviral sequences within the human host genome. Integration of viral-derived DNA occurs at preferential loci, suggesting a site-specific crosstalk between viral sequences and human genes. We here describe a genome engineering workflow to generate models for HIV-1 infection that for the first time recapitulate proviral integration at selected genomic loci and provide unique tools to study effects of HIV proviral integration site choice. Using this workflow, we have derived two BACH2-HIV-1 reporter models that mimic largely latent integration in the clinically relevant BACH2 gene locus, which has been associated with recurrent integration and HIV-reservoir maintenance in chronically infected patients...
March 14, 2018: Virus Research
Li Huang, Wei-Hong Lai, Lei Zhu, Wei Li, Lei Wei, Kuo-Hsiung Lee, Lan Xie, Chin-Ho Chen
We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo , which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1...
March 8, 2018: ACS Medicinal Chemistry Letters
Daniel Sauter, Frank Kirchhoff
HIV-1, the main causative agent of AIDS, and related primate lentiviruses show a striking ability to efficiently replicate throughout the lifetime of an infected host. In addition to their high variability, the acquisition of several accessory genes has enabled these viruses to efficiently evade or counteract seemingly strong antiviral immune responses. The respective viral proteins, i.e. Vif, Vpr, Vpu, Vpx and Nef, show a stunning functional diversity, acting by various mechanisms and targeting a large variety of cellular factors involved in innate and adaptive immunity...
February 23, 2018: Cytokine & Growth Factor Reviews
Harshana S De Silva Feelixge, Daniel Stone, Pavitra Roychoudhury, Martine Aubert, Keith R Jerome
Chronic viral infections remain a major public health issue affecting millions of people worldwide. Highly active antiviral treatments have significantly improved prognosis and infection-related morbidity and mortality, but have failed to eliminate persistent viral forms. Therefore, new strategies to either eradicate or control these viral reservoirs are paramount to allow patients to stop antiretroviral therapy and realize a cure. Viral genome disruption based on gene editing by programmable endonucleases is one promising curative gene therapy approach...
March 9, 2018: ACS Infectious Diseases
Jeffy George, Joseph J Mattapallil
Human immunodeficiency virus (HIV) establishes life-long latency in infected individuals. Although highly active antiretroviral therapy (HAART) has had a significant impact on the course of HIV infection leading to a better long-term outcome, the pool of latent reservoir remains substantial even under HAART. Numerous approaches have been under development with the goal of eradicating the latent HIV reservoir though with limited success. Approaches that combine immune-mediated control of HIV to activate both the innate and the adaptive immune system under suppressive therapy along with "shock and kill" drugs may lead to a better control of the reactivated virus...
2018: Frontiers in Immunology
Jesús Rodríguez-Muñoz, Santiago Moreno
The disadvantages of the long-term administration of antiretroviral therapy as well as the huge number of affected persons have placed the cure of HIV as a primary goal of Public Health. HIV may persist in the organism by at least four mechanisms: a latently infected cellular reservoir, the persistent replication of HIV in spite of ART, anatomic sanctuaries, and the immune dysfunction. Several strategies directed against these mechanisms have been developed. With all this, a complete eradication of HIV has been achieved in a patient using the transplantation of haemopoietic stem cells that were resistant to HIV-infection, and there are examples of functional cure either spontaneously (elite controllers) or after antiretroviral therapy (post-treatment controllers)...
March 3, 2018: Enfermedades Infecciosas y Microbiología Clínica
Chen Huan, Zhaolong Li, Shanshan Ning, Hong Wang, Xiao-Fang Yu, Wenyan Zhang
The HIV-1 reservoir is a major obstacle to complete eradication of the virus. Although many proteins and RNAs have been characterized as regulators in HIV-1/AIDS pathogenesis and latency, only a few long non-coding RNAs (lncRNAs) have been shown to be closely associated with HIV-1 replication and latency. Here, we demonstrated that lncRNA uc002yug.2 plays a key role in HIV-1 viral replication and latency. uc002yug.2 potentially enhances HIV-1 viral replication, LTR activity as well as the activation of latent HIV-1 in both cell lines and CD4+ T cells from patients...
February 28, 2018: Journal of Virology
Zheng Wang, Evelyn E Gurule, Timothy P Brennan, Jeffrey M Gerold, Kyungyoon J Kwon, Nina N Hosmane, Mithra R Kumar, Subul A Beg, Adam A Capoferri, Stuart C Ray, Ya-Chi Ho, Alison L Hill, Janet D Siliciano, Robert F Siliciano
The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to cure. Several lines of evidence suggest that the latent reservoir is maintained through cellular proliferation. Analysis of this proliferative process is complicated by the fact that most infected cells carry defective proviruses. Additional complications are that stimuli that drive T cell proliferation can also induce virus production from latently infected cells and productively infected cells have a short in vivo half-life. In this ex vivo study, we show that latently infected cells containing replication-competent HIV-1 can proliferate in response to T cell receptor agonists or cytokines that are known to induce homeostatic proliferation and that this can occur without virus production...
February 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
M Echchakery, J Nieto, S Boussaa, N El Fajali, S Ortega, K Souhail, H Aajly, C Chicharro, E Carrillo, J Moreno, A Boumezzough
In Morocco, visceral leishmaniasis (VL) is a parasitic disease caused by the flagellated protozoan parasite Leishmania infantum. L. infantum is transmitted by the bite of female phlebotomine sandflies, and its main reservoir hosts are domestic dogs. Asymptomatic infection with L. infantum is more frequent than clinically apparent disease. In HIV-infected patients, the risk of clinical VL is increased due to immunosuppression that may reactivate latent infections. However, coinfected subjects do not necessarily develop VL and may remain as asymptomatic carriers depending on their immune status...
February 24, 2018: Parasitology Research
Jin Gohda, Kazuo Suzuki, Kai Liu, Xialin Xie, Hiroaki Takeuchi, Jun-Ichiro Inoue, Yasushi Kawaguchi, Takaomi Ishida
HIV-1 latent reservoirs harbouring silenced but replication-competent proviruses are a major obstacle against viral eradication in infected patients. The "shock and kill" strategy aims to reactivate latent provirus with latency reversing agents (LRAs) in the presence of antiretroviral drugs, necessitating the development of effective and efficient LRAs. We screened a chemical library for potential LRAs and identified two dual Polo-like kinase (PLK)/bromodomain inhibitors, BI-2536 and BI-6727 (volasertib), which are currently undergoing clinical trials against various cancers...
February 23, 2018: Scientific Reports
Corinne Barat, Alizé Proust, Alexandre Deshiere, Mathieu Leboeuf, Jean Drouin, Michel J Tremblay
The "shock and kill" HIV-1 cure strategy proposes eradication of stable cellular reservoirs by clinical treatment with latency-reversing agents (LRAs). Although resting CD4+ T cells latently infected with HIV-1 constitute the main reservoir that is targeted by these approaches, their consequences on other reservoirs such as the central nervous system are still unknown and should be taken into consideration. We performed experiments aimed at defining the possible role of astrocytes in HIV-1 persistence in the brain and the effect of LRA treatments on this viral sanctuary...
February 21, 2018: Glia
Guochun Jiang, Don Nguyen, Nancie M Archin, Steven A Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M Elsheikh, George R Thompson, Dennis J Hartigan-O'Connor, David M Margolis, Joseph K Wong, Satya Dandekar
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2)...
February 19, 2018: Journal of Clinical Investigation
Vipul Gupta, Narendra M Dixit
Eradicating HIV-1 infection is difficult because of the reservoir of latently infected cells that gets established soon after infection, remains hidden from antiretroviral drugs and host immune responses, and retains the capacity to reignite infection following the cessation of treatment. Drugs called latency-reversing agents (LRAs) are being developed to reactivate latently infected cells and render them susceptible to viral cytopathicity or immune killing. Whereas individual LRAs have failed to induce adequate reactivation, pairs of LRAs have been identified recently that act synergistically and hugely increase reactivation levels compared to individual LRAs...
February 16, 2018: PLoS Computational Biology
Xiaolei Wang, Huanbin Xu
The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin...
2018: Frontiers in Immunology
Nadia Madrid-Elena, María Laura García-Bermejo, Sergio Serrano-Villar, Alberto Díaz-de Santiago, Beatriz Sastre, Carolina Gutiérrez, Fernando Dronda, María Coronel Díaz, Ester Domínguez, María Rosa López-Huertas, Beatriz Hernández-Novoa, Santiago Moreno
Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency reversing potential of maraviroc and the mechanisms involved, we performed a phase-II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (Eudra CT: 2012-003215-66). All patients completed full maraviroc dosing and follow up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signalling pathways involved in the viral reactivation...
February 14, 2018: Journal of Virology
Sheraz Khan, Mazhar Iqbal, Muhammad Tariq, Shahid M Baig, Wasim Abbas
HIV-1 latency allows the virus to persist until reactivation, in a transcriptionally silent form in its cellular reservoirs despite the presence of effective cART. Such viral persistence represents a major barrier to HIV eradication since treatment interruption leads to rebound plasma viremia. Polycomb group (PcG) proteins have recently got a considerable attention in regulating HIV-1 post-integration latency as they are involved in the repression of proviral gene expression through the methylation of histones...
2018: Clinical Epigenetics
Karine Dubé, Stuart Luter, Breanne Lesnar, Luke Newton, Jerome Galea, Brandon Brown, Sara Gianella
BACKGROUND: The landscape of Human Immunodeficiency Virus (HIV) research has changed drastically over the past three decades. With the remarkable success of antiretroviral treatment (ART) in decreasing AIDS-related mortality, some researchers have shifted their HIV research focus from treatment to cure research. The HIV cure research community often uses the term eradication to describe the science, and talks about eradicating the virus from the body. In public discourse, the term eradication could be conflated with disease eradication at the population level...
February 13, 2018: BMC Public Health
Zheng Wang, Francesco R Simonetti, Robert F Siliciano, Gregory M Laird
Antiretroviral therapy cannot cure HIV-1 infection due to the persistence of a small number of latently infected cells harboring replication-competent proviruses. Measuring persistent HIV-1 is challenging, as it consists of a mosaic population of defective and intact proviruses that can shift from a state of latency to active HIV-1 transcription. Due to this complexity, most of the current assays detect multiple categories of persistent HIV-1, leading to an overestimate of the true size of the latent reservoir...
February 13, 2018: Retrovirology
Julia Bergild McBrien, Nitasha A Kumar, Guido Silvestri
In this article, we summarize the role of CD8+ T cells during natural and ART-treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8+ T cell-based HIV cure strategies. Evidence suggests that CD8+ T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8+ T cells is responsible for control of viremia. However, it has been proposed that CD8+ T cells also use non-cytolytic mechanisms to control SIV infection...
February 10, 2018: European Journal of Immunology
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