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HIV gene therapy

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https://www.readbyqxmd.com/read/27905841/cell-delivered-entry-inhibitors-for-hiv-1-ccr5-downregulation-and-blocking-virus-membrane-fusion-in-defending-the-host-cell-population
#1
Geoff Symonds, Jeffrey S Bartlett, Hans-Peter Kiem, Marlene Tsie, Louis Breton
HIV-1 infection requires the presence of the CD4 receptor on the target cell surface and a coreceptor, predominantly CC-chemokine receptor 5 (CCR5). It has been shown that individuals who are homozygous for a defective CCR5 gene are protected from HIV-1 infection. A novel self-inactivating lentiviral vector LVsh5/C46 (Cal-1) has been engineered to block HIV-1 infection with two viral entry inhibitors, conferring resistance to HIV-1 infection from both CCR5 and CXCR4 tropic strains. Cal-1 encodes a short hairpin RNA (sh5) to downregulate CCR5 and C46, an HIV-1 fusion inhibitor...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27905840/combining-cell-and-gene-therapy-in-an-effort-to-eradicate-hiv
#2
Thor A Wagner
More than 30 million people are infected with HIV, and HIV remains the fifth leading cause of disability-adjusted life years worldwide. Antiretroviral therapy (ART) dramatically decreases mortality rate, but there are side effects, long-term toxicities, expenses, stigmas, and inconveniences associated with chronic treatment, and HIV-infected individuals on ART have an increased risk of malignancies, cardiovascular disease, neurologic disease, and shortened life expectancy. Therefore, a cure for HIV remains an important goal...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27905839/gene-therapy-to-cure-hiv-where-to-from-here
#3
Rowena Johnston
A variety of approaches are being tested to cure HIV, but with the exception of the Berlin patient case, none has been successful. The Berlin patient, positive for both HIV and acute myeloid leukemia (AML), received two stem cell transplants from a donor homozygous for the CCR5delta32 mutation. In the 8 years since his second transplant, he has remained free of both HIV and AML. This case provides strong proof-of-principle that a cure for HIV is possible and might be achieved through gene therapy. Several technological barriers must be resolved and are discussed here, including the safe delivery of the intervention throughout the body of the infected person, increased efficiency of gene editing, and avoidance of resistance to the therapy...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27905838/engineering-hiv-specific-immunity-with-chimeric-antigen-receptors
#4
Scott G Kitchen, Jerome A Zack
HIV remains a highly important public health and clinical issue despite many recent advances in attempting to develop a cure, which has remained elusive for most people infected with HIV. HIV disease can be controlled with pharmacologic therapies; however, these treatments are expensive, may have severe side effects, and are not curative. Consequently, an improved means to control or eliminate HIV replication is needed. Cytotoxic T lymphocytes (CTLs) play a critical role in controlling viral replication and are an important part in the ability of the immune response to eradicate most viral infections...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27901085/wide-variation-in-susceptibility-of-transmitted-founder-hiv-1-subtype-c-isolates-to-protease-inhibitors-and-association-with-in-vitro-replication-efficiency
#5
Katherine A Sutherland, Dami A Collier, Daniel T Claiborne, Jessica L Prince, Martin J Deymier, Richard A Goldstein, Eric Hunter, Ravindra K Gupta
The gag gene is highly polymorphic across HIV-1 subtypes and contributes to susceptibility to protease inhibitors (PI), a critical class of antiretrovirals that will be used in up to 2 million individuals as second-line therapy in sub Saharan Africa by 2020. Given subtype C represents around half of all HIV-1 infections globally, we examined PI susceptibility in subtype C viruses from treatment-naïve individuals. PI susceptibility was measured in a single round infection assay of full-length, replication competent MJ4/gag chimeric viruses, encoding the gag gene and 142 nucleotides of pro derived from viruses in 20 patients in the Zambia-Emory HIV Research Project acute infection cohort...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900346/preclinical-development-and-qualification-of-zfn-mediated-ccr5-disruption-in-human-hematopoietic-stem-progenitor-cells
#6
David L DiGiusto, Paula M Cannon, Michael C Holmes, Lijing Li, Anitha Rao, Jianbin Wang, Gary Lee, Philip D Gregory, Kenneth A Kim, Samuel B Hayward, Kathleen Meyer, Colin Exline, Evan Lopez, Jill Henley, Nancy Gonzalez, Victoria Bedell, Rodica Stan, John A Zaia
Gene therapy for HIV-1 infection is a promising alternative to lifelong combination antiviral drug treatment. Chemokine receptor 5 (CCR5) is the coreceptor required for R5-tropic HIV-1 infection of human cells. Deletion of CCR5 renders cells resistant to R5-tropic HIV-1 infection, and the potential for cure has been shown through allogeneic stem cell transplantation with naturally occurring homozygous deletion of CCR5 in donor hematopoietic stem/progenitor cells (HSPC). The requirement for HLA-matched HSPC bearing homozygous CCR5 deletions prohibits widespread application of this approach...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27898737/transcriptomic-analysis-implicates-the-p53-signaling-pathway-in-the-establishment-of-hiv-1-latency-in-central-memory-cd4-t-cells-in-an-in-vitro-model
#7
Cory H White, Bastiaan Moesker, Nadejda Beliakova-Bethell, Laura J Martins, Celsa A Spina, David M Margolis, Douglas D Richman, Vicente Planelles, Alberto Bosque, Christopher H Woelk
The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq...
November 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27894862/hiv-drug-resistance-testing-among-patients-failing-second-line-antiretroviral-therapy-comparison-of-in-house-and-commercial-sequencing
#8
Benjamin Chimukangara, Bhavini Varyani, Tinei Shamu, Junior Mutsvangwa, Justen Manasa, Elizabeth White, Cleophas Chimbetete, Ruedi Luethy, David Katzenstein
INTRODUCTION: HIV genotyping is often unavailable in low and middle-income countries due to infrastructure requirements and cost. We compared genotype resistance testing in patients with virologic failure, by amplification of HIV pol gene, followed by "in-house" sequencing and commercial sequencing. METHODS: Remnant plasma samples from adults and children failing second-line ART were amplified and sequenced using in-house and commercial di-deoxysequencing, and analyzed in Harare, Zimbabwe and at Stanford, U...
November 25, 2016: Journal of Virological Methods
https://www.readbyqxmd.com/read/27889981/chimeric-trojan-protein-insertion-in-lentiviral-membranes-makes-lentiviruses-susceptible-to-neutralisation-by-anti-tetanus-serum-antibodies
#9
Anita Le-Heron, Steve Patterson, Rafael J Yáñez-Muñoz, George Dickson
This study describes the initial testing of a novel strategy for neutralisation of lentiviruses using the fundamental biology of enveloped viruses' assembly and budding. In the field of gene therapy, viral vector surface proteins have been manipulated in order to redirect host cell specificity by alteration of pseudo-types. We tested whether known viral pseudo-typing proteins or surface proteins known to be recruited to the HIV envelope could be engineered to carry neutralising epitopes from another microorganism onto the lentiviral surface...
November 27, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27889708/mir-34a-is-a-common-link-in-both-hiv-and-antiretroviral-therapy-induced-vascular-aging
#10
Jiaxin Zhan, Shanshan Qin, Lili Lu, Xiamin Hu, Jun Zhou, Yeying Sun, Jian Yang, Ying Liu, Zunzhe Wang, Ning Tan, Jiyan Chen, Chunxiang Zhang
Both HIV and antiretroviral therapy could induce vascular aging with unclear mechanisms. In this study, via microarray analysis, we identified, for the first time, that miR-34a expression was significantly increased in both HIV-infected, and antiretroviral agents-treated vessels and vascular endothelial cells (ECs) from these vessels. In cultured ECs, miR-34a expression was significantly increased by HIV-Tat protein and by the antiretroviral agents, lopinavir/ritonavir. Both HIV-Tat protein and antiretroviral agents could induce EC senescence, which was inhibited by miR-34a inhibition...
November 26, 2016: Aging
https://www.readbyqxmd.com/read/27873361/effect-of-hiv-infection-in-the-microuclei-frequency-on-the-oral-mucosa
#11
Celina Faig Lima, Monica Ghislaine Oliveira Alves, Juvencio Jose Duailibe Furtado, Marcelo Marcucci, Ivan Balducci, Janete Dias Almeida
BACKGROUND: the genotoxic impact of HIV infection on the oral cavity malignancies is unknown. The aim of this study was to evaluate the effect of HIV infection in micronuclei (MN) frequency on the oral mucosa of HIV+ patients and establish a relationship with early cytogenetic changes in oral carcinogenesis. METHODS: 30 HIV + individuals who are under highly active antiretroviral therapy (HAART) and 30 non HIV patients were evaluated. Two smears were taken from the lateral border of the tongue and mouth floor and stained by Feulgen...
November 22, 2016: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/27869478/etravirine-and-rilpivirine-drug-resistance-among-hiv-1-subtype-c-infected-children-failing-non-nucleoside-reverse-transcriptase-inhibitor-based-regimens-in-south-india
#12
Shanmugam Saravanan, Bagavathi Kausalya, Selvamurthi Gomathi, Sathasivam Sivamalar, Balakrishnan Pachamuthu, Selvamuthu Poongulali, Ambrose Pradeep, Solomon S Sunil, Sarvode N Mothi, Davey M Smith, Rami Kantor
We have analyzed reverse transcriptase (RT) region of HIV-1 pol gene from 97 HIV-infected children who were identified as failing first-line therapy that included a first generation non-nucleoside reverse transcriptase inhibitors (Nevirapine and Efavirenz) for at least 6 months. We found that 54% and 65% of the children had genotypically predicted resistance to second generation non-nucleoside reverse transcriptase inhibitors drugs Etravirine and Rilpivirine, respectively. These cross-resistance mutations may compromise future NNRTI based regimens, especially in resource-limited settings...
November 21, 2016: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/27862491/alarmins-and-central-nervous-system-inflammation-in-hiv-associated-neurological-disorders
#13
M-L Gougeon
In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorders (HAND) persist in infected individuals with adequate immunological and virological status. Risk factors for cognitive impairment include hepatitis C virus co-infection, host genetic factors predisposing to HAND, the early establishment of the virus in the CNS and its persistence under HAART; thus, the CNS is an important reservoir for HIV. Microglial cells are permissive to HIV-1, and NLRP3 inflammasome-associated genes were found expressed in brains of HIV-1-infected persons, contributing to brain disease...
November 16, 2016: Journal of Internal Medicine
https://www.readbyqxmd.com/read/27861240/semen-bacterial-concentrations-and-hiv-1-rna-shedding-among-hiv-1-seropositive-kenyan-men
#14
Christine Korhonen, Sujatha Srinivasan, Dandi Huang, Daisy L Ko, Eduard J Sanders, Norbert M Peshu, John N Krieger, Charles H Muller, Robert W Coombs, David N Fredricks, Susan M Graham
INTRODUCTION: HIV-1 is transmitted through semen from men to their sexual partners. Genital infections can increase HIV-1 RNA shedding in semen, but shedding also occurs in the absence of typical pathogens. We hypothesized that higher bacterial concentrations in semen would be associated with higher HIV-1 RNA levels. METHODS: We analyzed semen samples from 42 HIV-1 seropositive Kenyan men using quantitative PCR to assess bacterial concentrations and real-time PCR to measure HIV-1 RNA levels...
November 14, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/27858889/correlates-of-infection-and-molecular-characterization-of-blood-borne-hiv-hcv-and-hbv-infections-in-hiv-1-infected-inmates-in-italy-an-observational-cross-sectional-study
#15
Nunzia Sanarico, Stefania D'Amato, Roberto Bruni, Claudia Rovetto, Emanuela Salvi, Patrizia Di Zeo, Paola Chionne, Elisabetta Madonna, Giulio Pisani, Angela Costantino, Michele Equestre, Maria E Tosti, Alessandra Cenci, Maria T Maggiorella, Leonardo Sernicola, Emanuele Pontali, Alfredo Pansera, Rocco Quattrocchi, Sergio Carbonara, Fabio Signorile, Lorenzo Antonio Surace, Guido Federzoni, Elisa Garlassi, Giulio Starnini, Roberto Monarca, Sergio Babudieri, Maria Rapicetta, Maria G Pompa, Anna Caraglia, Barbara Ensoli, Anna R Ciccaglione, Stefano Buttò
Coinfection of blood-borne hepatitis B and hepatitis C viruses (HBV and HCV, respectively) in human immunodeficiency virus type 1 (HIV-1)-positive individuals frequently occurs in inmate population and peculiar viral strains and patterns of virological markers may be observed.Plasma from 69 HIV-1-positive inmates was obtained from 7 clinical centers connected with correctional centers in different towns in Italy. HIV, HBV, and HCV markers were tested by commercial assays. Virus genotyping was carried out by sequencing the protease and reverse transcriptase-encoding region (PR-RT region) for HIV and a region encompassing the NS5B gene for HCV and subsequent phylogenetic analysis...
November 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27855071/high-prevalence-of-pneumocystis-jirovecii-dihydropteroate-synthase-gene-mutations-in-patients-with-first-episode-of-pneumocystis-pneumonia-in-santiago-chile-and-their-clinical-response-to-trimethoprim-sulfamethoxazole-therapy
#16
Carolina A Ponce, Magali Chabé, Claudio George, Alejandra Cárdenas, Luisa Duran, Julia Guerrero, Rebeca Bustamante, Olga Matos, Laurence Huang, Robert F Miller, Sergio L Vargas
Mutations in the Dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii associate with failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs, or be acquired via person-to-person transmission. DHPS mutations raise concern about decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with first-episode of PCP from 2002-2010 in Santiago, Chile...
November 14, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27854119/clinical-applications-of-genome-editing-to-hiv-cure
#17
Cathy X Wang, Paula M Cannon
Despite significant advances in HIV drug treatment regimens, which grant near-normal life expectancies to infected individuals who have good virological control, HIV infection itself remains incurable. In recent years, novel gene- and cell-based therapies have gained increasing attention due to their potential to provide a functional or even sterilizing cure for HIV infection with a one-shot treatment. A functional cure would keep the infection in check and prevent progression to AIDS, while a sterilizing cure would eradicate all HIV viruses from the patient...
December 2016: AIDS Patient Care and STDs
https://www.readbyqxmd.com/read/27842871/trends-in-drug-resistance-associated-mutations-in-a-real-life-cohort-of-italian-patients-infected-with-hiv-1
#18
Claudia Montagna, Laura Mazzuti, Francesca Falasca, Paola Maida, Mauro Bucci, Gabriella D'Ettorre, Ivano Mezzaroma, Alessandra Fantauzzi, Nadia Alvaro, Vincenzo Vullo, Guido Antonelli, Ombretta Turriziani
Recent studies support the idea that human immunodeficiency virus type 1 (HIV-1) drug resistance is declining in developed countries. To help assess the current situation in Italy, the dynamics of drug resistance mutations in pol and integrase genes in plasma samples from HIV-1-positive patients attending Sapienza University Hospital, Rome, from 2003 to 2014 were analysed. In total, 1730 genotype resistance tests (GRTs) were retrospectively analysed. The prevalence of major drug resistance mutations (DRMs) was evaluated over time in the global population and in patients with antiretroviral therapy (ART) failure...
December 2015: Journal of Global Antimicrobial Resistance
https://www.readbyqxmd.com/read/27819062/reconstitution-of-peripheral-t-cells-by-tissue-derived-ccr4-central-memory-cells-following-hiv-1-antiretroviral-therapy
#19
Yolanda D Mahnke, Kipper Fletez-Brant, Irini Sereti, Mario Roederer
BACKGROUND: Highly active antiretroviral therapy induces clinical benefits to HIV-1 infected individuals, which can be striking in those with progressive disease. Improved survival and decreased incidence of opportunistic infections go hand in hand with a suppression of the plasma viral load, an increase in peripheral CD4(+) T-cell counts, as well as a reduction in the activation status of both CD4(+) and CD8(+) T cells. METHODS: We investigated T-cell dynamics during ART by polychromatic flow cytometry in total as well as in HIV-1-specific CD4(+) and CD8(+) T cells in patients with advanced disease...
2016: Pathogens & Immunity
https://www.readbyqxmd.com/read/27807176/hiv-tat-impairs-neurogenesis-through-functioning-as-a-notch-ligand-and-activation-of-notch-signaling-pathway
#20
Yan Fan, Xiang Gao, Jinhui Chen, Ying Liu, Johnny J He
: Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain...
November 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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