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Latent hiv reservoir

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https://www.readbyqxmd.com/read/28210784/novel-aids-therapies-based-on-gene-editing
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28194140/hiv-1-tat-and-viral-latency-what-we-can-learn-from-naturally-occurring-sequence-variations
#4
REVIEW
Doreen Kamori, Takamasa Ueno
Despite the effective use of antiretroviral therapy, the remainder of a latently HIV-1-infected reservoir mainly in the resting memory CD4(+) T lymphocyte subset has provided a great setback toward viral eradication. While host transcriptional silencing machinery is thought to play a dominant role in HIV-1 latency, HIV-1 protein such as Tat, may affect both the establishment and the reversal of latency. Indeed, mutational studies have demonstrated that insufficient Tat transactivation activity can result in impaired transcription of viral genes and the establishment of latency in cell culture experiments...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28183626/stavudine-loaded-gelatin-liposomes-for-hiv-therapy-preparation-characterization-and-in-vitro-cytotoxic-evaluation
#5
Debasis Nayak, Ankita Boxi, Sarbani Ashe, Neethi Chandra Thathapudi, Bismita Nayak
Despite continuous research and availability of 25 different active compounds for treating chronic HIV-1 infection, there is no absolute cure for this deadly disease. Primarily, the residual viremia remains hidden in latently infected reservoir sites and persistently release the viral RNA into the blood stream. The study proposes the dual utilization of the prepared stavudine-containing nanoformulations to control the residual viremia as well as target the reservoir sites. Gelatin nanoformulations containing very low dosage of stavudine were prepared through classical desolvation process and were later loaded in soya lecithin-liposomes...
April 1, 2017: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/28181540/hiv-related-proteins-prolong-macrophage-survival-through-induction-of-triggering-receptor-expressed-on-myeloid-cells-1
#6
Zhihong Yuan, Xian Fan, Bashar Staitieh, Chetna Bedi, Paul Spearman, David M Guidot, Ruxana T Sadikot
Triggering receptor expressed on myeloid cells-1(TREM-1) is a member of the superimmunoglobulin receptor family. We have previously shown that TREM-1 prolongs survival of macrophages treated with lipoolysaccharide through Egr2-Bcl2 signaling. Recent studies suggest a role for TREM-1 in viral immunity. Human immunodeficiency virus-1 (HIV) targets the monocyte/macrophage lineage at varying stages of infection. Emerging data suggest that macrophages are key reservoirs for latent HIV even in individuals on antiretroviral therapy...
February 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28179531/toll-like-receptor-7-agonist-gs-9620-induces-hiv-expression-and-hiv-specific-immunity-in-cells-from-hiv-infected-individuals-on-suppressive-antiretroviral-therapy
#7
Angela Tsai, Alivelu Irrinki, Jasmine Kaur, Tomas Cihlar, George Kukolj, Derek D Sloan, Jeffrey P Murry
Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs)...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28178277/paucity-of-intact-non-induced-provirus-with-early-long-term-antiretroviral-therapy-of-perinatal-hiv-infection
#8
Kaitlin Rainwater-Lovett, Carrie Ziemniak, Douglas Watson, Katherine Luzuriaga, George Siberry, Ann Petru, YaHui Chen, Priyanka Uprety, Margaret McManus, Ya-Chi Ho, Susanna L Lamers, Deborah Persaud
The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults...
2017: PloS One
https://www.readbyqxmd.com/read/28176813/a-combinational-crispr-cas9-gene-editing-approach-can-halt-hiv-replication-and-prevent-viral-escape
#9
Robert Jan Lebbink, Dorien C M de Jong, Femke Wolters, Elisabeth M Kruse, Petra M van Ham, Emmanuel J H J Wiertz, Monique Nijhuis
HIV presents one of the highest evolutionary rates ever detected and combination antiretroviral therapy is needed to overcome the plasticity of the virus population and control viral replication. Conventional treatments lack the ability to clear the latent reservoir, which remains the major obstacle towards a cure. Novel strategies, such as CRISPR/Cas9 gRNA-based genome-editing, can permanently disrupt the HIV genome. However, HIV genome-editing may accelerate viral escape, questioning the feasibility of the approach...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28166799/toll-like-receptor-3-activation-selectively-reverses-hiv-latency-in-microglial-cells
#10
David Alvarez-Carbonell, Yoelvis Garcia-Mesa, Stephanie Milne, Biswajit Das, Curtis Dobrowolski, Roxana Rojas, Jonathan Karn
BACKGROUND: Multiple toll-like receptors (TLRs) are expressed in cells of the monocytic lineage, including microglia, which constitute the major reservoir for human immunodeficiency virus (HIV) infection in the brain. We hypothesized that TLR receptor mediated responses to inflammatory conditions by microglial cells in the central nervous system (CNS) are able to induce latent HIV proviruses, and contribute to the etiology of HIV-associated neurocognitive disorders. RESULTS: Newly developed human microglial cell lines (hµglia), obtained by immortalizing human primary microglia with simian virus-40 (SV40) large T antigen and the human telomerase reverse transcriptase, were used to generate latently infected cells using a single-round HIV virus carrying a green fluorescence protein reporter (hµglia/HIV, clones HC01 and HC69)...
February 6, 2017: Retrovirology
https://www.readbyqxmd.com/read/28161963/effects-of-heme-degradation-products-on-reactivation-of-latent-hiv-1
#11
P Shankaran, M Madlenakova, V Hajkova, D Jilich, I Svobodova, A Horinek, Y Fujikura, Z Melkova
Human immunodeficiency virus (HIV-1) infection can be currently controlled by combined antiretroviral therapy, but a sterilizing cure is not achievable as this therapy does not target persistent HIV-1 in latent reservoirs. Therefore, different latency reversal agents are intensively explored in various models. We have previously observed that heme arginate, a drug approved for human use, reveals a strong synergism with PKC inducers in reactivation of the latent provirus. Heme is physiologically decomposed by heme oxygenases into 3 degradation products: iron (Fe2+), carbon monoxide (CO) and biliverdin which is further converted to bilirubin by biliverdin reductase...
February 6, 2017: Acta Virologica
https://www.readbyqxmd.com/read/28152074/multiple-ubxn-family-members-inhibit-retrovirus-and-lentivirus-production-and-canonical-nf%C3%AE%C2%BA%C3%AE-signaling-by-stabilizing-i%C3%AE%C2%BAb%C3%AE
#12
Yani Hu, Kaitlin O'Boyle, Jim Auer, Sagar Raju, Fuping You, Penghua Wang, Erol Fikrig, Richard E Sutton
UBXN proteins likely participate in the global regulation of protein turnover, and we have shown that UBXN1 interferes with RIG-I-like receptor (RLR) signaling by interacting with MAVS and impeding its downstream effector functions. Here we demonstrate that over-expression of multiple UBXN family members decreased lentivirus and retrovirus production by several orders-of-magnitude in single cycle assays, at the level of long terminal repeat-driven transcription, and three family members, UBXN1, N9, and N11 blocked the canonical NFκB pathway by binding to Cullin1 (Cul1), inhibiting IκBα degradation...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28147284/benzotriazoles-reactivate-latent-hiv-1-through-inactivation-of-stat5-sumoylation
#13
Alberto Bosque, Kyle A Nilson, Amanda B Macedo, Adam M Spivak, Nancie M Archin, Ryan M Van Wagoner, Laura J Martins, Camille L Novis, Matthew A Szaniawski, Chris M Ireland, David M Margolis, David H Price, Vicente Planelles
The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release...
January 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/28145571/a-significant-productive-in-vivo-infection-of-resting-cells-with-simian-immunodeficiency-virus-in-a-macaque-with-aids
#14
Bapi Pahar, Wendy Lala, Dot Kuebler, David Liu
Identifying the cells that can be infected with HIV in vivo and thus potentially persist as latent reservoirs is of high priority. Here, we report the major infected cells in a chronically simian immunodeficiency virus (SIV)-infected macaque that developed AIDS and encephalitis. A majority of the infected cells were detected as non-proliferating resting cells. SIV-infected non-proliferating resting cells were found to be playing an important role in viral pathogenesis, persistence, or reservoir formation.
February 1, 2017: Journal of Medical Primatology
https://www.readbyqxmd.com/read/28128885/mechanisms-of-hiv-persistence-in-hiv-reservoirs
#15
REVIEW
Mayibongwe L Mzingwane, Caroline T Tiemessen
The establishment and maintenance of HIV reservoirs that lead to persistent viremia in patients on antiretroviral drugs remains the greatest challenge of the highly active antiretroviral therapy era. Cellular reservoirs include resting memory CD4+ T lymphocytes, implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals, persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia...
January 27, 2017: Reviews in Medical Virology
https://www.readbyqxmd.com/read/28103248/effect-of-the-latent-reservoir-on-the-evolution-of-hiv-at-the-within-and-between-host-levels
#16
Hilje M Doekes, Christophe Fraser, Katrina A Lythgoe
The existence of long-lived reservoirs of latently infected CD4+ T cells is the major barrier to curing HIV, and has been extensively studied in this light. However, the effect of these reservoirs on the evolutionary dynamics of the virus has received little attention. Here, we present a within-host quasispecies model that incorporates a long-lived reservoir, which we then nest into an epidemiological model of HIV dynamics. For biologically plausible parameter values, we find that the presence of a latent reservoir can severely delay evolutionary dynamics within a single host, with longer delays associated with larger relative reservoir sizes and/or homeostatic proliferation of cells within the reservoir...
January 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28097226/ifitm1-targets-hiv-1-latently-infected-cells-for-antibody-dependent-cytolysis
#17
Rui André Saraiva Raposo, Miguel de Mulder Rougvie, Dominic Paquin-Proulx, Phillip M Brailey, Vinicius D Cabido, Paul M Zdinak, Allison S Thomas, Szu-Han Huang, Greta A Beckerle, Richard B Jones, Douglas F Nixon
HIV-1 persistence in latent reservoirs during antiretroviral therapy (ART) is the main obstacle to virus eradication. To date, there is no marker that adequately identifies latently infected CD4(+) T cells in vivo. Using a well-established ex vivo model, we generated latently infected CD4(+) T cells and identified interferon-induced transmembrane protein 1 (IFITM1), a transmembrane antiviral factor, as being overexpressed in latently infected cells. By targeting IFITM1, we showed the efficient and specific killing of a latently infected cell line and CD4(+) T cells from ART-suppressed patients through antibody-dependent cytolysis...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28073694/hiv-latency-should-we-shock-or-lock
#18
REVIEW
Gilles Darcis, Benoit Van Driessche, Carine Van Lint
Combinatory antiretroviral therapy (cART) increases the survival and quality of life of HIV-1-infected patients. However, interruption of therapy almost invariably leads to the re-emergence of detectable viral replication because HIV-1 persists in viral latent reservoirs. Improved understanding of the molecular mechanisms involved in HIV-1 latency has paved the way for innovative strategies that attempt to purge latent virus. In this article we discuss the results of the broadly explored 'shock and kill' strategy, and also highlight the major hurdles facing this approach...
January 7, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/27998285/are-t-cells-the-only-hiv-1-reservoir
#19
REVIEW
Abraham Joseph Kandathil, Sho Sugawara, Ashwin Balagopal
Current antiretroviral therapies have improved the duration and quality of life of people living with HIV-1. However, viral reservoirs impede complete eradication of the virus. Although there are many strategies to eliminate infectious virus, the most actively pursued are latency reversing agents in conjunction with immune modulation. This strategy, known as "shock and kill", has been tested primarily against the most widely recognized HIV-1 latent reservoir found in resting memory CD4+ T cells. This is in part because of the dearth of conclusive evidence about the existence of non-T cell reservoirs...
December 20, 2016: Retrovirology
https://www.readbyqxmd.com/read/27993846/nonnucleoside-reverse-transcriptase-inhibitors-reduce-hiv-1-virus-production-from-latently-infected-resting-cd4-t-cells-following-latency-reversal
#20
Jennifer M Zerbato, Gilda Tachedjian, Nicolas Sluis-Cremer
Therapeutic strategies that target the latent HIV-1 reservoir in resting CD4+ T cells of infected-individuals are always administered in the presence of combination antiretroviral therapy. Using a primary cell of HIV-1 latency, we evaluated whether different antiviral drug classes affected latency reversal (as assessed by extracellular virus production) by anti-CD3/CD28 monoclonal antibodies or by bryostatin 1. We found that the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine significantly decreased HIV-1 production by ≥ 1 log...
December 19, 2016: Antimicrobial Agents and Chemotherapy
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