Specific properties of shRNA-mediated CCR5 downregulation that enhance the inhibition of HIV-1 infection in combination with shRNA targeting HIV-1 rev

2021 ◽  
Author(s):  
Maria E Cardona ◽  
Jorma Hinkula ◽  
Kristin Gustafsson ◽  
Birger Christensson ◽  
Britta Wahren ◽  
...  
Keyword(s):  
Infected Individual ◽  
Antiviral Effect ◽  
Endogenous Virus ◽  
Ccr5 Expression ◽  
Hairpin Rna ◽  
Escape Mutants ◽  
Human Ccr5 ◽  
Hiv 1 ◽  
Selection Of ◽  
Better Than

Abstract Treatment with RNAi against HIV-1 transcripts efficiently inhibits viral replication but induces selection of escape mutants; therefore, the CCR5 coreceptor was suggested as an additional target. Blocking viral and host transcripts improved the antiviral effect. We have used short hairpin RNA (shRNA) targeting the human CCR5 (shCCR5) or the HIV-1 rev (shRev) transcripts to demonstrate distinctive properties of anti-CCR5 shRNA: shCCR5 induced more sustained protection than shRev; partial reduction in CCR5 expression substantially decreased HIV-1 infection, and shCCR5 performed better than shRev in the mixed shRNA-treated and untreated cultures. These observations indicate that CCR5 inhibitors should be conveniently included in HIV-1 gene silencing treatment schedules when only a certain cell fraction is protected to further reduce endogenous virus in a properly ART-treated HIV-1 infected individual.

scholarly journals Relationship between Functional Profile of HIV-1 Specific CD8 T Cells and Epitope Variability with the Selection of Escape Mutants in Acute HIV-1 Infection

2011 ◽  
Vol 7 (2) ◽  
pp. e1001273 ◽  
Author(s):  
Guido Ferrari ◽  
Bette Korber ◽  
Nilu Goonetilleke ◽  
Michael K. P. Liu ◽  
Emma L. Turnbull ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Functional Profile ◽  
Escape Mutants ◽  
Acute Hiv ◽  
Hiv 1 ◽  
Selection Of

scholarly journals A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1534-1544 ◽  
Author(s):  
Saki Shimizu ◽  
Patrick Hong ◽  
Balamurugan Arumugam ◽  
Lauren Pokomo ◽  
Joshua Boyer ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Lentiviral Vector ◽  
Short Hairpin Rna ◽  
Lymphoid Organs ◽  
Great Promise ◽  
Ccr5 Expression ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Hiv 1

AbstractInhibiting the expression of the HIV-1 coreceptor CCR5 holds great promise for controlling HIV-1 infection in patients. Here we report stable knockdown of human CCR5 by a short hairpin RNA (shRNA) in a humanized bone marrow/liver/thymus (BLT) mouse model. We delivered a potent shRNA against CCR5 into human fetal liver-derived CD34+ hematopoietic progenitor/stem cells (HPSCs) by lentiviral vector transduction. We transplanted vector-transduced HPSCs solidified with Matrigel and a thymus segment under the mouse kidney capsule. Vector-transduced autologous CD34+ cells were subsequently injected in the irradiated mouse, intended to create systemic reconstitution. CCR5 expression was down-regulated in human T cells and monocytes/macrophages in systemic lymphoid tissues, including gut-associated lymphoid tissue, the major site of HIV-1 replication. The shRNA-mediated CCR5 knockdown had no apparent adverse effects on T-cell development as assessed by polyclonal T-cell receptor Vβ family development and naive/memory T-cell differentiation. CCR5 knockdown in the secondary transplanted mice suggested the potential of long-term hematopoietic reconstitution by the shRNA-transduced HPSCs. CCR5 tropic HIV-1 infection was effectively inhibited in mouse-derived human splenocytes ex vivo. These results demonstrate that lentiviral vector delivery of shRNA into human HPSCs could stably down-regulate CCR5 in systemic lymphoid organs in vivo.

scholarly journals Selection of Potent Non-Toxic Inhibitory Sequences from a Randomized HIV-1 Specific Lentiviral Short Hairpin RNA Library

PLoS ONE ◽  
2010 ◽  
Vol 5 (10) ◽  
pp. e13172 ◽  
Author(s):  
Carola Pongratz ◽  
Benjamin Yazdanpanah ◽  
Hamid Kashkar ◽  
Maik J. Lehmann ◽  
Hans-Georg Kräusslich ◽  
...  
Keyword(s):  
Short Hairpin Rna ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Hiv 1 ◽  
Selection Of

scholarly journals Restricting HIV-1 pathways for escape using rationally designed anti–HIV-1 antibodies

2013 ◽  
Vol 210 (6) ◽  
pp. 1235-1249 ◽  
Author(s):  
Ron Diskin ◽  
Florian Klein ◽  
Joshua A. Horwitz ◽  
Ariel Halper-Stromberg ◽  
D. Noah Sather ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Consensus Sequence ◽  
Complex Structure ◽  
Infected Individual ◽  
Viral Escape ◽  
Effective Vaccine ◽  
Therapeutic Approaches ◽  
Escape Mutants ◽  
Anti Hiv ◽  
Hiv 1

Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46G54W variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46G54W–resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti–HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2–gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46G54W arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1YU-2–infected humanized mice, with viremic control exhibited when a third antibody, 10–1074, was added to the combination.

scholarly journals Different In Vivo Effects of HIV-1 Immunodominant Epitope-Specific Cytotoxic T Lymphocytes on Selection of Escape Mutant Viruses

2010 ◽  
Vol 84 (11) ◽  
pp. 5508-5519 ◽  
Author(s):  
Hirokazu Koizumi ◽  
Masao Hashimoto ◽  
Mamoru Fujiwara ◽  
Hayato Murakoshi ◽  
Takayuki Chikata ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Neutralizing Antibodies ◽  
Escape Mutant ◽  
Escape Mutants ◽  
Hiv 1 ◽  
Selection Of ◽  
Strong Ability

ABSTRACT HIV-1 escape mutants are well known to be selected by immune pressure via HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies. The ability of the CTLs to suppress HIV-1 replication is assumed to be associated with the selection of escape mutants from the CTLs. Therefore, we first investigated the correlation between the ability of HLA-A*1101-restricted CTLs recognizing immunodominant epitopes in vitro and the selection of escape mutants. The result showed that there was no correlation between the ability of these CTLs to suppress HIV-1 replication in vitro and the appearance of escape mutants. The CTLs that had a strong ability to suppress HIV-1 replication in vitro but failed to select escape mutants expressed a higher level of PD-1 in vivo, whereas those that had a strong ability to suppress HIV-1 replication in vitro and selected escape mutants expressed a low level of PD-1. Ex vivo analysis of these CTLs revealed that the latter CTLs had a significantly stronger ability to recognize the epitope than the former ones. These results suggest that escape mutations are selected by HIV-1-specific CTLs that have a stronger ability to recognize HIV-1 in vivo but not in vitro.

scholarly journals CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants

2015 ◽  
Vol 96 (7) ◽  
pp. 1899-1905 ◽  
Author(s):  
Hanna Dreja ◽  
Corinna Pade ◽  
Lei Chen ◽  
Áine McKnight
Keyword(s):  
Binding Site ◽  
Neutralizing Antibody ◽  
Cd4 Binding Site ◽  
Escape Mutants ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1 ◽  
Selection Of

Implementasi Voip Server Berbasis IPV6 Dengan Raspberry PI

2019 ◽  
Vol 9 (01) ◽  
pp. 47-54
Author(s):  
Rabbai San Arif ◽  
Yuli Fitrisia ◽  
Agus Urip Ari Wibowo
Keyword(s):  
Internet Protocol ◽  
Wireless Transmission ◽  
Raspberry Pi ◽  
Test Results ◽  
Average Delay ◽  
Ipv6 Network ◽  
Ip Network ◽  
Selection Of ◽  
Better Than

Voice over Internet Protocol (VoIP) is a telecommunications technology that is able to pass the communication service in Internet Protocol networks so as to allow communicating between users in an IP network. However VoIP technology still has weakness in the Quality of Service (QoS). VOPI weaknesses is affected by the selection of the physical servers used. In this research, VoIP is configured on Linux operating system with Asterisk as VoIP application server and integrated on a Raspberry Pi by using wired and wireless network as the transmission medium. Because of depletion of IPv4 capacity that can be used on the network, it needs to be applied to VoIP system using the IPv6 network protocol with supports devices. The test results by using a wired transmission medium that has obtained are the average delay is 117.851 ms, jitter is 5.796 ms, packet loss is 0.38%, throughput is 962.861 kbps, 8.33% of CPU usage and 59.33% of memory usage. The analysis shows that the wired transmission media is better than the wireless transmission media and wireless-wired.

Effect of Contact Ratio on Spur Gear Dynamic Load With No Tooth Profile Modifications

1996 ◽  
Vol 118 (3) ◽  
pp. 439-443 ◽  
Author(s):  
Chuen-Huei Liou ◽  
Hsiang Hsi Lin ◽  
F. B. Oswald ◽  
D. P. Townsend
Keyword(s):  
Dynamic Load ◽  
Spur Gear ◽  
Tooth Size ◽  
Contact Ratio ◽  
Gear Dynamics ◽  
Wide Range ◽  
Gear Contact ◽  
Center Distance ◽  
Selection Of ◽  
Better Than

This paper presents a computer simulation showing how the gear contact ratio affects the dynamic load on a spur gear transmission. The contact ratio can be affected by the tooth addendum, the pressure angle, the tooth size (diametral pitch), and the center distance. The analysis presented in this paper was performed by using the NASA gear dynamics code DANST. In the analysis, the contact ratio was varied over the range 1.20 to 2.40 by changing the length of the tooth addendum. In order to simplify the analysis, other parameters related to contact ratio were held constant. The contact ratio was found to have a significant influence on gear dynamics. Over a wide range of operating speeds, a contact ratio close to 2.0 minimized dynamic load. For low-contact-ratio gears (contact ratio less than two), increasing the contact ratio reduced gear dynamic load. For high-contact-ratio gears (contact ratio equal to or greater than 2.0), the selection of contact ratio should take into consideration the intended operating speeds. In general, high-contact-ratio gears minimized dynamic load better than low-contact-ratio gears.

scholarly journals Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3821
Author(s):  
Rita Meleddu ◽  
Angela Corona ◽  
Simona Distinto ◽  
Filippo Cottiglia ◽  
Serenella Deplano ◽  
...  
Keyword(s):  
Single Agent ◽  
Hiv Reverse Transcriptase ◽  
Substitution Pattern ◽  
Associated Functions ◽  
Dual Inhibition ◽  
Hiv Rt ◽  
Therapeutic Protocols ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Selection Of

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.

scholarly journals Insights in Behavior of Variably Formulated Alginate-Based Microcapsules for Cell Transplantation

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Pia Montanucci ◽  
Silvia Terenzi ◽  
Claudio Santi ◽  
Ilaria Pennoni ◽  
Vittorio Bini ◽  
...  
Keyword(s):  
Divalent Cations ◽  
Chemical Properties ◽  
Live Cells ◽  
High Performing ◽  
Physical Chemical ◽  
Degenerative Disorders ◽  
Selection Of ◽  
Better Than

Alginate-based microencapsulation of live cells may offer the opportunity to treat chronic and degenerative disorders. So far, a thorough assessment of physical-chemical behavior of alginate-based microbeads remains cloudy. A disputed issue is which divalent cation to choose for a high performing alginate gelling process. Having selected, in our system, high mannuronic (M) enriched alginates, we studied different gelling cations and their combinations to determine their eventual influence on physical-chemical properties of the final microcapsules preparation,in vitroandin vivo. We have shown that used of ultrapure alginate allows for high biocompatibility of the formed microcapsules, regardless of gelation agents, while use of different gelling cations is associated with corresponding variable effects on the capsules’ basic architecture, as originally reported in this work. However, only the final application which the capsules are destined to will ultimately guide the selection of the ideal, specific gelling divalent cations, since in principle there are no capsules that are better than others.

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