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https://www.readbyqxmd.com/read/29770863/siv-latency-in-macrophages-in-the-cns
#1
Lucio Gama, Celina Abreu, Erin N Shirk, Suzanne E Queen, Sarah E Beck, Kelly A Metcalf Pate, Brandon T Bullock, M Christine Zink, Joseph L Mankowski, Janice E Clements
Lentiviruses infect myeloid cells, leading to acute infection followed by persistent/latent infections not cleared by the host immune system. HIV and SIV are lentiviruses that infect CD4+ lymphocytes in addition to myeloid cells in blood and tissues. HIV infection of myeloid cells in brain, lung, and heart causes tissue-specific diseases that are mostly observed during severe immunosuppression, when the number of circulating CD4+ T cells declines to exceeding low levels. Antiretroviral therapy (ART) controls viral replication but does not successfully eliminate latent virus, which leads to viral rebound once ART is interrupted...
May 17, 2018: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/29762173/a-defucosylated-bispecific-multivalent-molecule-exhibits-broad-hiv-1-neutralizing-activity-and-enhanced-adcc-against-reactivated-hiv-1-latently-infected-cells
#2
Desheng Kong, Yan Wang, Ping Ji, Wei Li, Tianlei Ying, Jinghe Huang, Chen Wang, Yanling Wu, Yanping Wang, Weizao Chen, Yanling Hao, Kunxue Hong, Yiming Shao, Dimiter S Dimitrov, Shibo Jiang, Liying Ma
OBJECTIVE: Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody-dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the non-defucosylated molecule LSEVh-LS...
May 11, 2018: AIDS
https://www.readbyqxmd.com/read/29762162/genetic-characterization-of-the-hiv-1-reservoir-after-vacc-4x-and-romidepsin-therapy-in-hiv-1-infected-individuals
#3
Anni Winckelmann, Vincent Morcilla, Wei Shao, Mariane H Schleimann, Jesper F Højen, Timothy E Schlub, Paul W Denton, Lars Østergaard, Ole S Søgaard, Martin Tolstrup, Sarah Palmer
OBJECTIVE: Therapeutic HIV-1 immunization followed by latency reversal has been suggested as a strategy to eradicate HIV-1. Here we investigate the phylogenetic composition of the HIV-1 regions targeted by the therapeutic HIV-1 peptide vaccine Vacc-4x in participants in a clinical trial. DESIGN: Seventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of Vacc-4x followed by three doses of romidepsin. Seven study participants were selected for sequencing analysis...
May 11, 2018: AIDS
https://www.readbyqxmd.com/read/29751762/hiv-latency-reversing-agents-act-through-tat-post-translational-modifications
#4
Georges Khoury, Talia M Mota, Shuang Li, Carolin Tumpach, Michelle Y Lee, Jonathan Jacobson, Leigh Harty, Jenny L Anderson, Sharon R Lewin, Damian F J Purcell
BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing...
May 11, 2018: Retrovirology
https://www.readbyqxmd.com/read/29746296/pd-1-contributes-to-the-establishment-and-maintenance-of-hiv-1-latency
#5
Vanessa A Evans, Renée M Van Der Sluis, Ajantha Solomon, Ashanti Dantanarayana, Catriona McNeil, Roger Garsia, Sarah Palmer, Rémi Fromentin, Nicolas Chomont, Rafick-Pierre Sékaly, Paul U Cameron, Sharon R Lewin
OBJECTIVE: In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T-cells expressing immune checkpoint molecules (ICs), in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo. METHODS: HIV latency was established in vitro following co-culture of resting CD4 T-cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1 and PD-1 non-proliferating CD4 memory T-cells...
May 9, 2018: AIDS
https://www.readbyqxmd.com/read/29720521/short-term-pifn-%C3%AE-2a-treatment-does-not-significantly-reduce-the-viral-reservoir-of-siv-infected-art-treated-rhesus-macaques
#6
David Palesch, Steven E Bosinger, Maud Mavigner, James M Billingsley, Cameron Mattingly, Diane Carnathan, Mirko Paiardini, Ann Chahroudi, Thomas Vanderford, Guido Silvestri
The major obstacle to HIV-1 eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and causes rapid viral rebound if treatment is interrupted. Type I interferons are immunomodulatory cytokines that induce antiviral factors and have been evaluated for the treatment of HIV-infected individuals, resulting in moderate reduction of viremia and inconclusive data about their effect on reservoir size. Here, we assessed the potential of pegylated IFN-α2a (pIFN-α2a) to reduce the viral reservoir in SIV-infected, ART-treated rhesus macaques (RMs)...
May 2, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29720517/antiviral-activity-of-hiv-gp120-targeting-bispecific-t-cell-engager-bite%C3%A2-antibody-constructs
#7
Johannes Brozy, Erika Schlaepfer, Christina K S Mueller, Mary-Aude Rochat, Silvana K Rampini, Renier Myburgh, Tobias Raum, Peter Kufer, Patrick A Baeuerle, Markus Muenz, Roberto F Speck
Today's gold standard in HIV therapy is the combined antiretroviral therapy (cART). It requires strict adherence by patients and life-long medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency, but cannot cure patients. The bispecific T cell engaging (BiTE®) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. We here generated BiTE® antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1+2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ϵ scFv...
May 2, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29720451/tlr7-agonists-induce-transient-viremia-and-reduce-the-viral-reservoir-in-siv-infected-rhesus-macaques-on-antiretroviral-therapy
#8
So-Yon Lim, Christa E Osuna, Peter T Hraber, Joe Hesselgesser, Jeffrey M Gerold, Tiffany L Barnes, Srisowmya Sanisetty, Michael S Seaman, Mark G Lewis, Romas Geleziunas, Michael D Miller, Tomas Cihlar, William A Lee, Alison L Hill, James B Whitney
Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29717016/sun2-modulates-hiv-1-infection-and-latency-through-association-with-lamin-a-c-to-maintain-the-repressive-chromatin
#9
Wei-Wei Sun, Shi Jiao, Li Sun, Zhaocai Zhou, Xia Jin, Jian-Hua Wang
The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5'-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host's modulation of HIV-1 transcription and latency...
May 1, 2018: MBio
https://www.readbyqxmd.com/read/29714165/distinct-chromatin-functional-states-correlate-with-hiv-latency-reactivation-in-infected-primary-cd4-t-cells
#10
Emilie Battivelli, Matthew S Dahabieh, Mohamed Abdel-Mohsen, J Peter Svensson, Israel Tojal Da Silva, Lillian B Cohn, Andrea Gramatica, Steven Deeks, Warner C Greene, Satish K Pillai, Eric Verdin
Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4+ T cells and determined which latently infected cells are reactivatable by current candidate LRAs...
May 1, 2018: ELife
https://www.readbyqxmd.com/read/29706951/transcriptional-modulation-of-human-endogenous-retroviruses-in-primary-cd4-t-cells-following-vorinostat-treatment
#11
Cory H White, Nadejda Beliakova-Bethell, Steven M Lada, Michael S Breen, Tara P Hurst, Celsa A Spina, Douglas D Richman, John Frater, Gkikas Magiorkinis, Christopher H Woelk
The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29694901/single-cell-rna-seq-reveals-transcriptional-heterogeneity-in-latent-and-reactivated-hiv-infected-cells
#12
Monica Golumbeanu, Sara Cristinelli, Sylvie Rato, Miguel Munoz, Matthias Cavassini, Niko Beerenwinkel, Angela Ciuffi
Despite effective treatment, HIV can persist in latent reservoirs, which represent a major obstacle toward HIV eradication. Targeting and reactivating latent cells is challenging due to the heterogeneous nature of HIV-infected cells. Here, we used a primary model of HIV latency and single-cell RNA sequencing to characterize transcriptional heterogeneity during HIV latency and reactivation. Our analysis identified transcriptional programs leading to successful reactivation of HIV expression.
April 24, 2018: Cell Reports
https://www.readbyqxmd.com/read/29689537/hiv-infection-advances-toward-a-cure
#13
Daniel C Douek
Achieving cure of HIV infection requires eliminating all replication-competent virus from the reservoir of latently infected cells or completely inhibiting infected cells from emerging from latency. Strategies include very early use of antiretroviral therapy; hematopoietic stem cell transplantation; "shock-and-kill" approaches; immune therapy with immune checkpoint inhibitors; gene therapy, including use of CC chemokine receptor 5-modified CD4+ T cells; and broadly neutralizing antibody therapy. Success is likely to require a combination of approaches...
April 2018: Topics in Antiviral Medicine
https://www.readbyqxmd.com/read/29684085/the-kat5-acetyl-histone4-brd4-axis-silences-hiv-1-transcription-and-promotes-viral-latency
#14
Zichong Li, Uri Mbonye, Zeming Feng, Xiaohui Wang, Xiang Gao, Jonathan Karn, Qiang Zhou
The bromodomain protein Brd4 promotes HIV-1 latency by competitively inhibiting P-TEFb-mediated transcription induced by the virus-encoded Tat protein. Brd4 is recruited to the HIV LTR by interactions with acetyl-histones3 (AcH3) and AcH4. However, the precise modification pattern that it reads and the writer for generating this pattern are unknown. By examining a pool of latently infected proviruses with diverse integration sites, we found that the LTR characteristically has low AcH3 but high AcH4 content...
April 23, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29683434/tandem-bispecific-broadly-neutralizing-antibody-a-novel-approach-to-hiv-1-treatment
#15
Guido Ferrari
The last decade has led to a significant advance in our knowledge of HIV-1 latency and immunity. However, we are still not close to finding a cure for HIV-1. Although combination antiretroviral therapy (cART) has led to increased survival, almost close to that of the general population, it is still not curative. In the current issue of the JCI, Wu et al. studied the prophylactic and therapeutic potential of an engineered tandem bispecific broadly neutralizing antibody (bs-bnAb), BiIA-SG. This bnAb's breadth and potency were highly effective in protection and treatment settings, as measured by complete viremia control following direct infusion, as well as elimination of infected cells and delay in viral rebound when delivered with a recombinant vector...
April 23, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29679637/recent-stimulant-use-and-leukocyte-gene-expression-in-methamphetamine-users-with-treated-hiv-infection
#16
Adam W Carrico, Annesa Flentje, Kord Kober, Sulggi Lee, Peter Hunt, Elise D Riley, Steven Shoptaw, R N Elena Flowers, Samantha E Dilworth, Savita Pahwa, Bradley E Aouizerat
Stimulant use may accelerate HIV disease progression through biological and behavioral pathways. However, scant research with treated HIV-positive persons has examined stimulant-associated alterations in pathophysiologic processes relevant to HIV pathogenesis. In a sample of 55 HIV-positive, methamphetamine-using sexual minority men with a viral load less than 200 copies/mL, we conducted RNA sequencing to examine patterns of leukocyte gene expression in participants who had a urine sample that was reactive for stimulants (n = 27) as compared to those who tested non-reactive (n = 28)...
April 18, 2018: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29673219/hiv-tat-p-tefb-interaction-a-potential-target-for-novel-anti-hiv-therapies
#17
REVIEW
Kaori Asamitsu, Koh Fujinaga, Takashi Okamoto
Transcription is a crucial step in the life cycle of the human immunodeficiency virus type 1 (HIV 1) and is primarily involved in the maintenance of viral latency. Both viral and cellular transcription factors, including transcriptional activators, suppressor proteins and epigenetic factors, are involved in HIV transcription from the proviral DNA integrated within the host cell genome. Among them, the virus-encoded transcriptional activator Tat is the master regulator of HIV transcription. Interestingly, unlike other known transcriptional activators, Tat primarily activates transcriptional elongation and initiation by interacting with the cellular positive transcriptional elongation factor b (P-TEFb)...
April 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29672640/differential-impact-of-transplantation-on-peripheral-and-tissue-associated-viral-reservoirs-implications-for-hiv-gene-therapy
#18
Christopher W Peterson, Jianbin Wang, Claire Deleage, Sowmya Reddy, Jasbir Kaur, Patricia Polacino, Andreas Reik, Meei-Li Huang, Keith R Jerome, Shiu-Lok Hu, Michael C Holmes, Jacob D Estes, Hans-Peter Kiem
Autologous transplantation and engraftment of HIV-resistant cells in sufficient numbers should recapitulate the functional cure of the Berlin Patient, with applicability to a greater number of infected individuals and with a superior safety profile. A robust preclinical model of suppressed HIV infection is critical in order to test such gene therapy-based cure strategies, both alone and in combination with other cure strategies. Here, we present a nonhuman primate (NHP) model of latent infection using simian/human immunodeficiency virus (SHIV) and combination antiretroviral therapy (cART) in pigtail macaques...
April 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29670623/human-immune-system-mice-for-the-study-of-human-immunodeficiency-virus-type-1-infection-of-the-central-nervous-system
#19
REVIEW
Teresa H Evering, Moriya Tsuji
Immunodeficient mice transplanted with human cell populations or tissues, also known as human immune system (HIS) mice, have emerged as an important and versatile tool for the in vivo study of human immunodeficiency virus-type 1 (HIV-1) pathogenesis, treatment, and persistence in various biological compartments. Recent work in HIS mice has demonstrated their ability to recapitulate critical aspects of human immune responses to HIV-1 infection, and such studies have informed our knowledge of HIV-1 persistence and latency in the context of combination antiretroviral therapy...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29643247/the-pathway-to-establishing-hiv-latency-is-critical-to-how-latency-is-maintained-and-reversed
#20
Simin D Rezaei, Hao K Lu, J Judy Chang, Ajantha Rhodes, Sharon R Lewin, Paul U Cameron
HIV infection requires lifelong antiretroviral therapy because of the persistence of latently infected CD4+ T cells. Induction of viral expression from latently infected cells occurs following T cell receptor (TCR) activation but not all latently infected cells respond to TCR stimulation. We compared two models of latently infected cells using an enhanced green fluorescent protein (EGFP) reporter virus to infect CCL19 treated resting CD4+ (rCD4) T cells (pre-activation latency) or activated CD4+ T cells that returned to a resting state (post-activation latency)...
April 11, 2018: Journal of Virology
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