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HIV gene therapy

Jiehua Zhou, Daniel Lazar, Haitang Li, Xin Xia, Sangeetha Satheesan, Paige Charlins, Denis O'Mealy, Ramesh Akkina, Sheena Saayman, Marc S Weinberg, John J Rossi, Kevin V Morris
Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR)...
2018: Theranostics
Dominik Brado, Adetayo Emmanuel Obasa, George Mondinde Ikomey, Ruben Cloete, Kamalendra Singh, Susan Engelbrecht, Ujjwal Neogi, Graeme Brendon Jacobs
HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatment-naive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2...
March 16, 2018: Scientific Reports
Denise C Hsu, Kimberly F Breglio, Luxin Pei, Chun-Shu Wong, Bruno B Andrade, Virginia Sheikh, Margery Smelkinson, Constantinos Petrovas, Adam Rupert, Leonardo Gil-Santana, Adrian Zelazny, Steven M Holland, Kenneth Olivier, Daniel Barber, Irini Sereti
Background: Immune reconstitution inflammatory syndrome (IRIS) is an aberrant inflammatory response in individuals with advanced human immunodeficiency virus (HIV) infection, after antiretroviral therapy (ART) initiation. The pathogenesis of Mycobacterium avium complex (MAC)-associated IRIS has not been fully elucidated. Methods: We investigated monocyte and CD4+ T-cell responses in vitro, tumor necrosis factor (TNF) expression in tissues, and plasma cytokines and inflammatory markers, in 13 HIV-infected patients with MAC-IRIS and 14 HIV-uninfected patients with pulmonary MAC infection...
March 10, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Daniel Enosi Tuipulotu, Natalie E Netzler, Jennifer H Lun, Jason M Mackenzie, Peter A White
Norovirus infections are a significant health and economic burden globally, accounting for hundreds of millions of cases of acute gastroenteritis every year. In the absence of an approved norovirus vaccine, there is an urgent need to develop antivirals to treat chronic infections, and provide prophylactic therapy to limit viral spread during epidemics and pandemics. Toll-like receptor (TLR) agonists have been explored widely for their antiviral potential and several are progressing through clinical trials for the treatment of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and as adjuvants for norovirus virus-like particle (VLP) vaccines...
March 12, 2018: Antimicrobial Agents and Chemotherapy
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
Vinay Kumar, Joshua Mansfield, Rong Fan, Andrew MacLean, Jian Li, Mahesh Mohan
Intestinal epithelial barrier dysfunction is a well-known sequela of HIV/SIV infection that persists despite antiretroviral therapy. Although inflammation is a triggering factor, the underlying molecular mechanisms remain unknown. Emerging evidence suggests that epithelial barrier function is epigenetically regulated by inflammation-induced microRNAs (miRNAs). Accordingly, we profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium and identified 46 differentially expressed miRNAs (20 upregulated and 26 downregulated) in chronically SIV-infected rhesus macaques ( Macaca mulatta )...
March 7, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Anthony A Duplanty, Robert W Siggins, Timothy Allerton, Liz Simon, Patricia E Molina
Work from our group demonstrated that chronic binge alcohol (CBA)-induces mitochondrial gene dysregulation at end-stage disease of simian immunodeficiency virus (SIV) infection in antiretroviral therapy (ART) naïve rhesus macaques. Alterations in gene expression can disrupt mitochondrial homeostasis and in turn contribute to the risk of metabolic comorbidities characterized by loss of skeletal muscle (SKM) functional mass that are associated with CBA, human immunodeficiency virus (HIV) infection, and prolonged ART...
March 2018: Physiological Reports
Lu Yang, Fang Niu, Honghong Yao, Ke Liao, Xufeng Chen, Yeonhee Kook, Rong Ma, Guoku Hu, Shilpa Buch
Chronic neuroinflammation still remains a common underlying feature of HIV-infected patients on combined anti-retroviral therapy (cART). Previous studies have reported that despite near complete suppression of virus replication by cART, cytotoxic viral proteins such as HIV trans-activating regulatory protein (Tat) continue to persist in tissues such as the brain and the lymph nodes, thereby contributing, in part, to chronic glial activation observed in HIV-associated neurological disorders (HAND). Understanding how the glial cells cross talk to mediate neuropathology is thus of paramount importance...
March 1, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Hanh Thi Pham, Thibault Mesplède
Human immunodeficiency virus type 1 (HIV-1) infection remains a major health issue worldwide. In developed countries, antiretroviral therapy has extended its reach from treatment of people living with HIV-1 to post-exposure prophylaxis, treatment as prevention, and, more recently, pre-exposure prophylaxis. These healthcare strategies offer the epidemiological tools to curve the epidemic in rich settings and will be concomitantly implemented in developing countries. One of the remaining challenges is to identify an efficacious curative strategy...
2018: Drugs in Context
Gurmit Kaur Jagjit Singh, Steve Kaye, James C Abbott, Christoph Boesecke, Juergen Rockstroh, Myra O McClure, Mark Nelson
Background The epidemic of acute HCV infection among HIV-infected men who have sex with men (MSM) is ongoing. Transmission of drug-resistant variants (DRVs) after HCV treatment failure could pose a major threat to the effectiveness of future therapies. We determined the baseline prevalence of pre-existing DRVs in the HCV NS3 protease gene and their effects on the addition of telaprevir (TVR) to standard pegylated interferon and ribavirin (PEG-IFN/RBV) for acute HCV infection in individuals enrolled in a multicentre randomized controlled trial (2013 and 2014)...
March 1, 2018: HIV Clinical Trials
Alessandra Bandera, Michela Masetti, Massimiliano Fabbiani, Mara Biasin, Antonio Muscatello, Nicola Squillace, Mario Clerici, Andrea Gori, Daria Trabattoni
Background: Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome-related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Methods: Cross-sectional, case-control study. HIV-infected patients on ART for ≥24 months with HIV-RNA<50 cp/mL for ≥12 months were enrolled and defined as immunological responders (IR) or non-responders (INR) if CD4 count was ≥500 or ≤350 cells/μL, respectively...
2018: Frontiers in Immunology
Ewurama D A Owusu, Samson K Djonor, Charles A Brown, Martin P Grobusch, Petra F Mens
BACKGROUND: Plasmodium falciparum, the most dominant species in sub-Saharan Africa, causes the most severe clinical malaria manifestations. In resource-limited Ghana, where malaria and HIV geographically overlap, histidine-rich protein 2 (HRP2)-based rapid diagnostic test (RDT) is a faster, easier and cheaper alternative to clinical gold standard light microscopy. However, mutations in parasite hrp2 gene may result in missed infections, which have severe implications for malaria control...
February 23, 2018: Malaria Journal
Pere Domingo, José Miguel Gallego-Escuredo, Irene Fernández, Joan Villarroya, Ferran Torres, María Del Mar Gutierrez, María Gracia Mateo, Francesc Villarroya, Francesc Vidal, Marta Giralt, Joan Carles Domingo
BACKGROUND: Omega-3 fatty acids have the potential to decrease inflammation and modify gene transcription. Whether docosahexanoic acid (DHA) supplementation can modify systemic inflammatory and subcutaneous adipose tissue (SAT) gene expression in HIV-infected patients is unknown. METHODS: A randomized, double-blind, placebo-controlled trial that enrolled 84 antiretroviral-treated patients who had fasting TG levels from 2.26 to 5.65 mmol/l and received DHA or placebo for 48 weeks was performed (ClinicalTrials...
February 19, 2018: Cytokine
Sudeep P Pushpakom, Antonysunil Adaikalakoteswari, Andrew Owen, David J Back, Gyanendra Tripathi, Sudhesh Kumar, Philip McTernan, Munir Pirmohamed
BACKGROUND: Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose-response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects. METHODS: Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively...
February 1, 2018: Diabetes & Vascular Disease Research
Benjamin Bruno Policicchio, Paola Sette, Cuiling Xu, George Haret-Richter, Tammy Dunsmore, Ivona Pandrea, Ruy M Ribeiro, Cristian Apetrei
Two SIVmac251-infected rhesus macaques received tenofovir/emtricitabine with raltegravir intensification. Viral rebound occurred during treatment and sequencing of reverse transcriptase and integrase genes identified multiple resistance mutations. Similar to HIV infection, antiretroviral-resistance mutations may occur in SIV-infected nonhuman primates receiving nonsuppressive ART. As ART administration to nonhuman primates is currently dramatically expanding, fueled by both cure research and the study of HIV-related comorbidities, viral resistance should be factored in the study design and data interpretation...
2018: PloS One
Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, Zhiwei Chen
The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral drug therapy (cART). Here, we investigate the potential of an engineered tandem bi-specific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving two scFv binding domains of each parental bnAb, a single-gene-encoded tandem bs-bnAb, namely BiIA-SG, displayed significantly improved breadth and potency...
February 20, 2018: Journal of Clinical Investigation
Teresa H Evering
PURPOSE OF REVIEW: The HIV-1 envelope gene (env) has been an intense focus of investigation in the search for genetic determinants of viral entry and persistence in the central nervous system (CNS). RECENT FINDINGS: Molecular signatures of CNS-derived HIV-1 env reflect the immune characteristics and cellular constraints of the CNS compartment. Although more readily found in those with advanced HIV-1 and HIV-associated neurocognitive disorders (HAND), molecular signatures distinguishing CNS-derived quasispecies can be identified early in HIV-1 infection, in the presence or absence of combination antiretroviral therapy (cART), and are dynamic...
February 19, 2018: Current HIV/AIDS Reports
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
Oded Danziger, Tal Pupko, Eran Bacharach, Marcelo Ehrlich
Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known...
2018: Frontiers in Immunology
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