Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication

Takeuchi, Hiroaki; Ishii, Hiroshi; Kuwano, Tetsuya; Inagaki, Natsuko; Akari, Hirofumi; Matano, Tetsuro

doi:10.1186/1742-4690-9-3

Cited by 10 publications

(18 citation statements)

References 55 publications

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“…To ensure that simianized VRC07 (simVRC07) retained the neutralizing capacity of huVRC07, we compared their activities in an in vitro TZM-bl pseudovirus assay. On a panel of 11 clade A, B, and C HIV-1 isolates, simVRC07 showed only a modest reduction in potency (1.8-fold), measured as the geometric mean IC 50 titer, compared to huVRC07 IgG (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…Cyclosporine has been shown to inhibit SIV and HIV-1 replication in vitro (50)(51)(52). However, the inhibitory effects of cyclosporine were not a factor for our challenge, as these macaques were challenged 11 days after the cessation of CsA treatment (5.5 weeks after AAV injection), and all macaques given control AAV8 vectors after cyclosporine treatment became infected (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Neutralization curves were fit by using a five-parameter nonlinear regression equation calculated with JMP software (SAS, Cary, NC). The neutralization titers were calculated as the concentration of monoclonal antibody or the plasma dilution that inhibited 50% of the virus replication measured in infected cells cultured alone (IC 50 or ID 50 , respectively).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection

Saunders

Wang

Joyce

et al. 2015

J Virol

106

115

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Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 g/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled. Broadly neutralizing antibodies (bnAbs) arise in human immunodeficiency virus type 1 (HIV-1)-infected individuals to various degrees (1-3), but vaccination to elicit such antibodies remains a challenge (4-6). An increasing number of potent bnAbs have been isolated in recent years from HIV-infected individuals (7-12). These bnAbs represent potential components for passive immunization in humans based on the finding that they protect nonhuman primates at physiologically achievable concentrations (13-16).The transduction of long-lived cells with a viral vector encoding the heavy and light chain genes of bnAbs, also known as vectored immunoprophylaxis, aims to protect against HIV-1 infection by conferring expression of protective antibodies (17)(18)(19)(20). In particular, viral vectors derived from adeno-associated virus (AAV) have yielded sustained expression of multiple bnAbs in mice (17,20). These bnAbs confer neutralizing activity in the plasma of the mice and thereby protect humanized mice against intraperitoneal, intravenous, and mucosal HIV-1 challenge (20,21).Nonhuman primate models of HIV-1 infection represent the most appropriate model to assess the ability of antibodies to protect against infection (22-24). The comparable physiology of mucosal tissues, their relatively large size, and their similar immune system (25) give nonhuman primates distinct advantages over humanized mice for assessing the potential to protect against mucosal transmission of HIV-1 in humans. However, in the context of gene delivery, antibody persistence, localization, and protection against mucosal infection have not been well studied in nonhuman primates. A previous study conducted with nonhuman primates advanced this concept by using recombinant AAV1 vectors to deliver genes encoding antibody-like molecules called immunoadhesins (26). The immunoadhesins were expressed for Ͼ1

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection

Saunders

Wang

Joyce

et al. 2015

J Virol

106

115

View full text Add to dashboard Cite

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“…Virus supernatant was harvested at 48 h posttransfection and filtered through a 0.45-m-pore syringe filter. HIV-1 NL4-3 virus stock was prepared by transfection of HeLa cells as previously reported (23). Titers of the virus stocks were quantitated by HIV-1 CA (p24) enzyme-linked immunosorbent assay (ELISA) (ZeptMetrix Corporation, Buffalo, NY) and by determination of the reverse transcriptase (RT) activity (24).…”

Section: Methodsmentioning

confidence: 99%

A Carboxy-Terminally Truncated Human CPSF6 Lacking Residues Encoded by Exon 6 Inhibits HIV-1 cDNA Synthesis and Promotes Capsid Disassembly

Hori

Takeuchi

Saito

et al. 2013

J Virol

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Since HIV-1 replication is modulated at multiple stages by host cell factors, identification and characterization of those host cell factors are expected to contribute to the development of novel anti-HIV therapeutics. Previous studies showed that a C-terminally truncated cytosolic form of cleavage and polyadenylation-specific factor 6 (CPSF6-358) inhibits HIV-1 infection through interference with HIV-1 trafficking to the nucleus. Here we identified and characterized a different configuration of C-terminally truncated human CPSF6 (hCPSF6-375) through cDNA expression cloning coupled with ganciclovir-mediated lethal selection. Notably, hCPSF6-375, but not mouse CPSF6-358 (mCPSF6-358) as previously reported, remarkably interfered with viral cDNA synthesis after HIV-1 infection. Moreover, we found that hCPSF6-375 aberrantly accelerated the disassembly of the viral capsid in target cells, while CPSF6-358 did not. Sequence comparison of CPSF6-375 and CPSF6-358 cDNAs showed a lack of exon 6 and additional coding sequence for 54 amino acid residues in the C terminus of hCPSF6-375. Mutational analyses revealed that the residues encoded by exon 6, but not the C-terminal 54 residues in hCPSF6-375, is responsible for impaired viral cDNA synthesis by hCPSF6-375. This is the first report demonstrating a novel mode of HIV-1 inhibition by truncated forms of CPSF6 that involves rapid capsid disassembly and inhibition of viral cDNA synthesis. These findings could facilitate an increased understanding of viral cDNA synthesis in light of the viral capsid disassembly.

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“…At 8–10 months post inoculation, all four FIV-infected cats transitioned into the asymptomatic phase of infection where plasma and peripheral blood mononuclear cell (PBMC)-associated viral gag RNA became rare to undetectable. [7] The viral transcription status in the acute and chronic phases of FIV have been intensely documented in these cats. [8–10] Three of the FIV-infected cats have been considered to be progressors, demonstrating the typical immunopathologic hallmark of FIV-infection characterized by very low numbers of peripheral CD4+ T cells.…”

Section: Introductionmentioning

confidence: 99%

Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus

et al. 2017

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Feline immunodeficiency virus (FIV) infection in cats results in life-long viral persistence and progressive immunopathology. We have previously described a cohort of experimentally infected cats demonstrating a progressive decline of peripheral blood CD4+ T-cell over six years in the face of apparent peripheral viral latency. More recently we reported findings from this same cohort that revealed popliteal lymph node tissue as sites for ongoing viral replication suggesting that tissue reservoirs are important in FIV immunopathogenesis during the late asymptomatic phase of infection. Results reported herein characterize important tissue reservoirs of active viral replication during the late asymptomatic phase by examining biopsied specimens of spleen, mesenteric lymph node (MLN), and intestine from FIV-infected and uninfected control cats. Peripheral blood collected coincident with harvest of tissues demonstrated severe CD4+ T-cell depletion, undetectable plasma viral gag RNA and rarely detectable peripheral blood mononuclear cell (PBMC)-associated viral RNA (vRNA) by real-time PCR. However, vRNA was detectable in all three tissue sites from three of four FIV-infected cats despite the absence of detectable vRNA in plasma. A novel in situ hybridization assay identified B cell lymphoid follicular domains as microanatomical foci of ongoing FIV replication. Additionally, we demonstrated that CD4+ leukocyte depletion in tissues, and CD4+ and CD21+ leukocytes as important cellular reservoirs of ongoing replication. These findings revealed that tissue reservoirs support foci of ongoing viral replication, in spite of highly restricted viral replication in blood. Lentiviral eradication strategies will need address tissue viral reservoirs.

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Host cell species-specific effect of cyclosporine A on simian immunodeficiency virus replication

Cited by 10 publications

References 55 publications

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection

A Carboxy-Terminally Truncated Human CPSF6 Lacking Residues Encoded by Exon 6 Inhibits HIV-1 cDNA Synthesis and Promotes Capsid Disassembly

Peripheral and central immune cell reservoirs in tissues from asymptomatic cats chronically infected with feline immunodeficiency virus

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