Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

Überla, Klaus; Stahl–Hennig∥, Christiane; Böttiger, D.; Mätz‐Rensing, Kerstin; Kaup, F.‐J.; Li, J; Wa, Haseltine; Fleckenstein, B; Hunsmann, Gerhard; Öberg, Bo

doi:10.1073/pnas.92.18.8210

Cited by 122 publications

(124 citation statements)

References 33 publications

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“…As shown in Tables 1 and 2, this RT-SHIV was sensitive not only to three NNRTIs but also to NRTIs and PIs tested. The in vitro antiviral activity of NNRTIs in this study was comparable to other studies [19,24] against the RT-SHIV virus which was originally derived from the same source [23]. In addition, another RT-SHIV mne also showed a similar sensitivity to NNRTIs [26] as compared to this study.…”

Section: Discussionsupporting

confidence: 85%

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

et al. 2009

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BackgroundNon-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important category of drugs for both chemotherapy and prevention of human immunodeficiency virus type 1 (HIV-1) infection. However, current non-human primate (NHP) models utilizing simian immunodeficiency virus (SIV) or commonly used chimeric SHIV (SIV expressing HIV-1 envelope) are inadequate due to the insensitivity to NNRTIs. To develop a NHP model for evaluation of NNRTI compounds, we characterized a RT-SHIV virus that was assembled by replacing the SIVmac239 reverse transcriptase (RT) with that of HIV-1HXB2. Since RT-SHIV exhibited in vitro characteristics of high infectivity, CCR5-usage, and sensitivity to HIV-1 specific NNRTIs, this virus was thought to be suitable for mucosal transmission and then was used to carry out a vaginal transmission study in pigtail macaques (Macaca nemestrina).ResultsRT-SHIV exhibited in vitro characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For in vivo vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate) or left untreated before intravaginal inoculation with 500 or 1,000 TCID50 of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4+T cell depletion, and antiviral antibody response. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment.ConclusionThis chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti-HIV compounds. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.

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Section: Discussionsupporting

confidence: 85%

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

et al. 2009

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“…Studies of HIV-SIV chimeras indicate that HIV-1 regions in the 5Ј half of the genome are responsible for the observed restricted replication in macaque cells (35,46). However, HIV-SIV chimeras containing the HIV-1 reverse transcriptase replicate efficiently in rhesus macaques, indicating that this viral protein is not sufficient to mediate the postentry restriction (4,50). Additionally, because the viral Vif protein exerts its phenotypic effects in a manner dependent on the virus-producing cell (21,23), Vif is less likely to be involved in this species-specific block to HIV-1 infection, which is determined by the target cell rather than the virusproducing cell.…”

mentioning

confidence: 99%

Human and Simian Immunodeficiency Virus Capsid Proteins Are Major Viral Determinants of Early, Postentry Replication Blocks in Simian Cells

Owens

Yang

Göttlinger

et al. 2003

J Virol

135

124

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The cells of most Old World monkey species exhibit early, postentry restrictions on infection by human immunodeficiency virus type 1 (HIV-1) but not by simian immunodeficiency virus of macaques (SIVmac). Conversely, SIVmac, but not HIV-1, infection is blocked in most New World monkey cells. By using chimeric HIV-1/SIVmac viruses capable of a single round of infection, we demonstrated that a major viral determinant of this restriction is the capsid (CA) protein. The efficiency of early events following HIV-1 and SIVmac entry is apparently determined by the interaction of the incoming viral CA and species-specific host factors

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“…The first examples of SHIVs were SIV strains that encoded HIV-1 envelope in place of SIV envelope, such that vaccines or drugs could target this entry protein (Li et al, 1992;Luciw et al, 1995;Reimann et al, 1996;Shibata et al, 1991). More recently, the reverse transcriptase (RT) coding region of SIVs have been replaced with that of HIV-1 to produce RT-SHIV that can be targeted by RT inhibitors (Ambrose et al, 2004;Uberla et al, 1995). Both types of SHIVs have been shown to infect macaques after mucosal exposure, simulating sexual transmission (Lu et al, 1996;Turville et al, 2008).…”

Section: Nonhuman Primate Modelsmentioning

confidence: 99%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

Cited by 122 publications

References 33 publications

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

Human and Simian Immunodeficiency Virus Capsid Proteins Are Major Viral Determinants of Early, Postentry Replication Blocks in Simian Cells

Use of Animal Models for Anti-HIV Drug Development

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