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Latent hiv reservoir

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https://www.readbyqxmd.com/read/29789664/the-bet-bromodomain-inhibitor-apabetalone-induces-apoptosis-of-latent-hiv-1-reservoir-cells-following-viral-reactivation
#1
Xuan-Xuan Zhang, Jian Lin, Tai-Zhen Liang, Heng Duan, Xing-Hua Tan, Bao-Min Xi, Lin Li, Shu-Wen Liu
The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol...
May 22, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29781356/combating-the-hiv-reservoirs
#2
Guido van Marle, Deirdre L Church, Frank van der Meer, M John Gill
Impressive advances have been made in the treatment and management of HIV-1 infected individuals. Combination antiretroviral therapy (cART) has turned HIV-1 infection from an almost invariable deadly infectious disease, to a lifelong manageable infectious disease. However, a cure or vaccine has not been forthcoming. A major problem in HIV-1 infection is the persistent and latently infected cellular and tissue reservoirs. One of these reservoirs is the Gut Associated Lymphoid tissue (GALT), which has been the research focus of our group...
May 21, 2018: Biotechnology & Genetic Engineering Reviews
https://www.readbyqxmd.com/read/29780387/cd32-expressing-cd4-t-cells-are-phenotypically-diverse-and-can-contain-proviral-hiv-dna
#3
Genevieve E Martin, Matthew Pace, John P Thornhill, Chansavath Phetsouphanh, Jodi Meyerowitz, Morgane Gossez, Helen Brown, Natalia Olejniczak, Julianne Lwanga, Gita Ramjee, Pontiano Kaleebu, Kholoud Porter, Christian B Willberg, Paul Klenerman, Nneka Nwokolo, Julie Fox, Sarah Fidler, John Frater
Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+ CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low , CD32+ CD14+ , and CD32high ). Of note, CD4 negative enrichment kits remove the majority of CD4+ CD32+ T cells, potentially skewing subsequent analyses if used...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29770863/siv-latency-in-macrophages-in-the-cns
#4
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/29768175/targeting-the-latent-reservoir-for-hiv-1
#5
REVIEW
Srona Sengupta, Robert F Siliciano
Antiretroviral therapy can effectively block HIV-1 replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to a cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir...
May 15, 2018: Immunity
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
#6
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/29744964/peering-into-the-hiv-reservoir
#7
REVIEW
Marcial García, María J Buzón, José M Benito, Norma Rallón
The main obstacle to HIV eradication is the establishment of a long-term persistent HIV reservoir. Although several therapeutic approaches have been developed to reduce and eventually eliminate the HIV reservoir, only a few have achieved promising results. A better knowledge of the mechanisms involved in the establishment and maintenance of HIV reservoir is of utmost relevance for the design of new therapeutic strategies aimed at purging it with the ultimate goal of achieving HIV eradication or alternatively a functional cure...
May 9, 2018: Reviews in Medical Virology
https://www.readbyqxmd.com/read/29742434/live-imaging-of-hiv-1-transfer-across-t-cell-virological-synapse-to-epithelial-cells-that-promotes-stromal-macrophage-infection
#8
Fernando Real, Alexis Sennepin, Yonatan Ganor, Alain Schmitt, Morgane Bomsel
During sexual intercourse, HIV-1 crosses epithelial barriers composing the genital mucosa, a poorly understood feature that requires an HIV-1-infected cell vectoring efficient mucosal HIV-1 entry. Therefore, urethral mucosa comprising a polarized epithelium and a stroma composed of fibroblasts and macrophages were reconstructed in vitro. Using this system, we demonstrate by live imaging that efficient HIV-1 transmission to stromal macrophages depends on cell-mediated transfer of the virus through virological synapses formed between HIV-1-infected CD4+ T cells and the epithelial cell mucosal surface...
May 8, 2018: Cell Reports
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
#9
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/29720451/tlr7-agonists-induce-transient-viremia-and-reduce-the-viral-reservoir-in-siv-infected-rhesus-macaques-on-antiretroviral-therapy
#10
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/29714165/distinct-chromatin-functional-states-correlate-with-hiv-latency-reactivation-in-infected-primary-cd4-t-cells
#11
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/29706961/regulatory-t-cells-as-potential-targets-for-hiv-cure-research
#12
REVIEW
Adam J Kleinman, Ranjit Sivanandham, Ivona Pandrea, Claire A Chougnet, Cristian Apetrei
T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29704439/histone-deacetylase-inhibitor-chidamide-promotes-reactivation-of-latent-hiv-by-introducing-histone-acetylation
#13
Qiyuan Kuai, Xiaofan Lu, Zhixin Qiao, Rui Wang, Yanbing Wang, Sanxian Ye, Min He, Yu Wang, Tong Zhang, Hao Wu, Suping Ren, Qun Yu
Highly active antiretroviral therapy (HAART) can reduce the HIV viral load in the plasma to undetectable levels. However, due to the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor (HDACi) recently approved for cancer treatment by the China Food and Drug Administration (CFDA), to reactivate latent HIV-1 via histone acetylation. Viral reactivities of chidamide were accessed in two latent HIV pseudotype virus cell reporter systems (J-Lat Tat-GFP Clone A72 and TZM-bl), a latently infected full-length HIV virus cell system (U1/HIV), and resting CD4+ T cells from nine HIV-infected patients under HAART with undetectable viral load...
April 28, 2018: Journal of Medical Virology
https://www.readbyqxmd.com/read/29697469/broadly-neutralizing-antibodies-for-treatment-and-prevention-of-hiv-1-infection
#14
Yehuda Z Cohen, Marina Caskey
PURPOSE OF REVIEW: Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs. RECENT FINDINGS: Phase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile...
April 24, 2018: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/29694901/single-cell-rna-seq-reveals-transcriptional-heterogeneity-in-latent-and-reactivated-hiv-infected-cells
#15
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
#16
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/29686423/clonal-cd4-t-cells-in-the-hiv-1-latent-reservoir-display-a-distinct-gene-profile-upon-reactivation
#17
Lillian B Cohn, Israel T da Silva, Renan Valieris, Amy S Huang, Julio C C Lorenzi, Yehuda Z Cohen, Joy A Pai, Allison L Butler, Marina Caskey, Mila Jankovic, Michel C Nussenzweig
Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life1,2 , enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5 . We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART...
April 23, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29684085/the-kat5-acetyl-histone4-brd4-axis-silences-hiv-1-transcription-and-promotes-viral-latency
#18
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/29682300/latent-hiv-dynamics-and-implications-for-sustained-viral-suppression-in-the-absence-of-antiretroviral-therapy
#19
EDITORIAL
John M Murray
Objectives: The interaction between HIV and the immune system gives rise to a complex dynamical system. We therefore investigate whether delayed viral rebound after antiretroviral therapy (ART) interruption (ATI) may be due to an individual's viral-immune state being in a region of relative stability, and if so, how this can be extended. Methods: Using a mathematical model duplicating plasma viral levels, HIV DNA and immune homeostatic dynamics for individuals on ART commenced at either primary (PHI) or chronic (CHI) HIV infection, we investigate whether latent reservoir reductions and perturbations in other infected and uninfected memory CD4+ T cell subsets can delay viral rebound...
April 1, 2018: Journal of Virus Eradication
https://www.readbyqxmd.com/read/29672640/differential-impact-of-transplantation-on-peripheral-and-tissue-associated-viral-reservoirs-implications-for-hiv-gene-therapy
#20
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
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