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Latent hiv reservoir

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https://www.readbyqxmd.com/read/28446770/instability-of-8e5-calibration-standard-revealed-by-digital-pcr-risks-inaccurate-quantification-of-hiv-dna-in-clinical-samples-by-qpcr
#1
Eloise Busby, Alexandra S Whale, R Bridget Ferns, Paul R Grant, Gary Morley, Jonathan Campbell, Carole A Foy, Eleni Nastouli, Jim F Huggett, Jeremy A Garson
Establishing a cure for HIV is hindered by the persistence of latently infected cells which constitute the viral reservoir. Real-time qPCR, used for quantification of this reservoir by measuring HIV DNA, requires external calibration; a common choice of calibrator is the 8E5 cell line, which is assumed to be stable and to contain one HIV provirus per cell. In contrast, digital PCR requires no external calibration and potentially provides 'absolute' quantification. We compared the performance of qPCR and dPCR in quantifying HIV DNA in 18 patient samples...
April 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28437703/antiviral-treatment-strategies-based-on-gene-silencing-and-genome-editing
#2
REVIEW
Roger Badia, Ester Ballana, José A Esté, Eva Riveira-Muñoz
The ability of some viruses to establish latently infected chronic reservoirs that escape to immune control becomes a major roadblock that impedes the cure of these infections. Therefore, new alternatives are needed to pursuit the eradication of viral persistent infections. Gene silencing technologies are in constant evolution and provide an outstanding sequence specificity that allows targeting any coding sequence of interest. Here we provide an overview of the development of gene silencing technologies ranging from initially RNA interference to the recently developed CRISPR/Cas9 and their potential as new antiviral strategies focusing on the eradication of HIV...
April 21, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28435692/a-cd3-cd28-microbead-based-hiv-1-viral-outgrowth-assay
#3
EDITORIAL
Yury V Kuzmichev, Rebecca T Veenhuis, Christopher W Pohlmeyer, Caroline C Garliss, Victoria Ek Walker-Sperling, Joel N Blankson
AIMS: Latently infected resting CD4 T cells represent a major barrier to HIV-1 eradication efforts. The standard assays used for measuring this reservoir induce activation of resting CD4 T cells with either phytohaemagglutinin (PHA) with irradiated feeder cells, or with anti-CD3 antibodies. We designed a study to compare the sensitivity of a new assay (based on the stimulation of CD4 T cells with anti-CD3 and anti-CD28 coated microbeads) with that of the traditional PHA- and feeder-based viral outgrowth assay...
April 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28435691/interrupting-antiretroviral-treatment-in-hiv-cure-research-scientific-and-ethical-considerations
#4
EDITORIAL
Samual A Garner, Stuart Rennie, Jintanat Ananworanich, Karine Dube, David M Margolis, Jeremy Sugarman, Randall Tressler, Adam Gilbertson, Liza Dawson
Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions...
April 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28431490/new-challenges-in-therapeutic-vaccines-against-hiv-infection
#5
Lorna Leal, Constanza Lucero, Josep M Gatell, Teresa Gallart, Montserrat Plana, Felipe García
There is a growing interest in developing curative strategies for HIV infection. Therapeutic vaccines are one of the most promising approaches. We will review the current knowledge and the new challenges in this research field. Areas covered: PubMed and ClinicalTrial.gov databases were searched to review the progress and prospects for clinical development of immunotherapies aimed to cure HIV infection. Dendritic cells (DC)-based vaccines have yielded the best results in the field. However, major immune-virologic barriers may hamper current vaccine strategies...
April 21, 2017: Expert Review of Vaccines
https://www.readbyqxmd.com/read/28426533/hiv-dna-content-in-different-cd4-t-cell-subsets-correlates-with-cd4-cd8-ratio-or-length-of-efficient-treatment
#6
Lara Gibellini, Simone Pecorini, Sara de Biasi, Elena Bianchini, Margherita Digaetano, Marcello Pinti, Gianluca Carnevale, Vanni Borghi, Giovanni Guaraldi, Cristina Mussini, Andrea Cossarizza, Milena Nasi
OBJECTIVES: HIV establishes a latent infection at different degrees within naïve (TN) or central (TCM) and effector memory (TEM) CD4+ T cell. Studying patients in whom HIV production was suppressed by combined antiretroviral therapy (cART), our main aim was to find which factors are related or can influence intracellular viral reservoir in different CD4+ T cell subsets. METHODS: We enrolled 32 HIV+ patients successfully treated for > 2 years, with a CD4+ T cell count > 500 cells/μL and plasma viremia undetectable from at least one year...
April 19, 2017: AIDS
https://www.readbyqxmd.com/read/28423333/hunting-down-the-hiv-1-reservoir-a-starring-role-for-antibodies
#7
Hugo Mouquet
The persistence of viruses "hidden" in a reservoir of latently infected CD4(+) T cells under antiretroviral therapy is the major obstacle to an HIV-1 cure. Recently published in Nature, two seminal studies from Descours et al. (2017) and Nishimura et al. (2017) bring hope for tracking and possibly eradicating the HIV-1 reservoir.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28388353/deficiency-in-dna-damage-response-a-new-characteristic-of-cells-infected-with-latent-hiv-1
#8
Dorota Piekna-Przybylska, Gaurav Sharma, Sanjay B Maggirwar, Robert A Bambara
Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells...
April 7, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28348204/hiv-persistence-through-division
#9
Lillian B Cohn, Michel C Nussenzweig
A long-lived latent reservoir for HIV-1 persists in CD4(+) T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.
April 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28341641/proliferation-of-latently-infected-cd4-t-cells-carrying-replication-competent-hiv-1-potential-role-in-latent-reservoir-dynamics
#10
Nina N Hosmane, Kyungyoon J Kwon, Katherine M Bruner, Adam A Capoferri, Subul Beg, Daniel I S Rosenbloom, Brandon F Keele, Ya-Chi Ho, Janet D Siliciano, Robert F Siliciano
A latent reservoir for HIV-1 in resting CD4(+) T lymphocytes precludes cure. Mechanisms underlying reservoir stability are unclear. Recent studies suggest an unexpected degree of infected cell proliferation in vivo. T cell activation drives proliferation but also reverses latency, resulting in productive infection that generally leads to cell death. In this study, we show that latently infected cells can proliferate in response to mitogens without producing virus, generating progeny cells that can release infectious virus...
April 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28331083/maintenance-of-the-hiv-reservoir-is-antagonized-by-selective-bcl2-inhibition
#11
Nathan W Cummins, Amy M Sainski-Nguyen, Sekar Natesampillai, Fatma Aboulnasr, Scott Kaufmann, Andrew D Badley
Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV infected cells. This expansion reflects homeostatic proliferation of infected cells by IL-7 or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate BAK to induce apoptosis of infected cells...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28297712/cd32a-is-a-marker-of-a-cd4-t-cell-hiv-reservoir-harbouring-replication-competent-proviruses
#12
Benjamin Descours, Gaël Petitjean, José-Luis López-Zaragoza, Timothée Bruel, Raoul Raffel, Christina Psomas, Jacques Reynes, Christine Lacabaratz, Yves Levy, Olivier Schwartz, Jean Daniel Lelievre, Monsef Benkirane
The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells...
March 15, 2017: Nature
https://www.readbyqxmd.com/read/28279508/tuberculosis-elimination-and-the-challenge-of-latent-tuberculosis
#13
REVIEW
Alberto Matteelli, Giorgia Sulis, Susanna Capone, Lia D'Ambrosio, Giovanni Battista Migliori, Haileyesus Getahun
Latent tuberculosis infection (LTBI) affects one third to one fourth of the human population and is the reservoir for a significant proportion of emerging active tuberculosis (TB) cases, especially in low incidence countries. The World Health Organization launched in 2015 the END-TB strategy that aims at TB elimination and promotes, for the first time ever, the management of LTBI. The preventive package, basically consisting of testing and treatment for LTBI in groups at high risk of reactivation, is a mainstay of the first pillar of the strategy, alongside prompt diagnosis and early treatment of both drug-susceptible and drug-resistant TB disease...
March 2017: La Presse Médicale
https://www.readbyqxmd.com/read/28279181/a-mature-macrophage-is-a-principal-hiv-1-cellular-reservoir-in-humanized-mice-after-treatment-with-long-acting-antiretroviral-therapy
#14
Mariluz Araínga, Benson Edagwa, R Lee Mosley, Larisa Y Poluektova, Santhi Gorantla, Howard E Gendelman
BACKGROUND: Despite improved clinical outcomes seen following antiretroviral therapy (ART), resting CD4+ T cells continue to harbor latent human immunodeficiency virus type one (HIV-1). However, such cells are not likely the solitary viral reservoir and as such defining where and how others harbor virus is imperative for eradication measures. To such ends, we used HIV-1ADA-infected NOD.Cg-Prkdc (scid) Il2rg (tm1Wjl) /SzJ mice reconstituted with a human immune system to explore two long-acting ART regimens investigating their abilities to affect viral cell infection and latency...
March 9, 2017: Retrovirology
https://www.readbyqxmd.com/read/28275460/reactivation-of-hiv-1-proviruses-in-immune-compromised-mice-engrafted-with-human-voa-negative-cd4-t-cells
#15
EDITORIAL
Zhe Yuan, Guobin Kang, Wuxun Lu, Qingsheng Li
BACKGROUND: HIV-1 infection remains incurable on antiretroviral therapy (ART) due to virus latency. To date, enhanced co-culture assays, including viral outgrowth assays (VOA), are commonly used to measure HIV-1 latent reservoirs and evaluate latency-reversing agents (LRAs). However, VOA can only reactivate a small fraction of intact proviruses. METHODS: To explore the utility of NOD scid gamma (NSG) mice as an in vivo model to reactivate HIV-1 proviruses from VOA-negative CD4+ T cells, resting CD4+ T cells from an HIV-1 latently infected individual were isolated and the human CD4+ T cells corresponding to VOA-positive and VOA-negative CD4+ T cells were engrafted into NSG mice...
January 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28246360/multiple-histone-lysine-methyltransferases-are-required-for-the-establishment-and-maintenance-of-hiv-1-latency
#16
Kien Nguyen, Biswajit Das, Curtis Dobrowolski, Jonathan Karn
We showed previously that the histone lysine methyltransferase (HKMT) H3K27me3 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PRC2) and is required for the maintenance of HIV-1 latency in Jurkat T cells. Here we show, by using chromatin immunoprecipitation experiments, that both PRC2 and euchromatic histone-lysine N-methyltransferase 2 (EHMT2), the G9a H3K9me2-3 methyltransferase, are highly enriched at the proviral 5' long terminal repeat (LTR) and rapidly displaced upon proviral reactivation...
February 28, 2017: MBio
https://www.readbyqxmd.com/read/28239658/loss-of-immune-homeostasis-dictates-shiv-rebound-after-stem-cell-transplantation
#17
Christopher W Peterson, Clarisse Benne, Patricia Polacino, Jasbir Kaur, Cristina E McAllister, Abdelali Filali-Mouhim, Willi Obenza, Tiffany A Pecor, Meei-Li Huang, Audrey Baldessari, Robert D Murnane, Ann E Woolfrey, Keith R Jerome, Shiu-Lok Hu, Nichole R Klatt, Stephen DeRosa, Rafick P Sékaly, Hans-Peter Kiem
The conditioning regimen used as part of the Berlin patient's hematopoietic cell transplant likely contributed to his eradication of HIV infection. We studied the impact of conditioning in simian-human immunodeficiency virus-infected (SHIV-infected) macaques suppressed by combination antiretroviral therapy (cART). The conditioning regimen resulted in a dramatic, but incomplete depletion of CD4(+) and CD8(+) T cells and CD20(+) B cells, increased T cell activation and exhaustion, and a significant loss of SHIV-specific Abs...
February 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28210784/novel-aids-therapies-based-on-gene-editing
#18
REVIEW
Kamel Khalili, Martyn K White, Jeffrey M Jacobson
HIV/AIDS remains a major public health issue. In 2014, it was estimated that 36.9 million people are living with HIV worldwide, including 2.6 million children. Since the advent of combination antiretroviral therapy (cART), in the 1990s, treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS has become increasingly rare. However, while people with HIV can expect to live a normal life span with cART, lifelong medication is required and cardiovascular, renal, liver, and neurologic diseases are still possible, which continues to prompt research for a cure for HIV...
February 16, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28202759/relationship-between-measures-of-hiv-reactivation-and-the-decline-of-latent-reservoir-under-latency-reversing-agents
#19
Janka Petravic, Thomas A Rasmussen, Sharon R Lewin, Stephen J Kent, Miles P Davenport
Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRA) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRA are explored in clinical trials, it becomes increasingly important to assess the effect of increased HIV reactivation rate on the decline of latently infected cells, and estimate LRA efficacy in increasing virus reactivation...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28194154/the-role-of-cd4-t-follicular-helper-cells-in-hiv-infection-from-the-germinal-center-to-the-periphery
#20
REVIEW
John Patrick Thornhill, Sarah Fidler, Paul Klenerman, John Frater, Chansavath Phetsouphanh
T follicular helper cells (TFh) are key components of the adaptive immune system; they are primarily found in germinal centers (GCs) where their interaction with B cells supports humoral immune responses and efficient antibody production. They are defined by the expression of CXC receptor 5, program death-1, ICOS, and secretion of IL-21. Their differentiation is regulated by B-cell lymphoma 6. The relationship and function of circulating TFh to bona fide TFh resident in the GC is much debated. HIV infection impacts the TFh response with evidence of aberrant TFh function observed in acute and chronic infection...
2017: Frontiers in Immunology
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