Cargando…

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

BACKGROUND: Non-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 comm...

Descripción completa

Detalles Bibliográficos
Autores principales: Jiang, Yonghou, Tian, Baoping, Saifuddin, Mohammed, Agy, Michael B, Emau, Peter, Cairns, J Scott, Tsai, Che-Chung
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780452/
https://www.ncbi.nlm.nih.gov/pubmed/19891783
http://dx.doi.org/10.1186/1742-6405-6-23
_version_ 1782174488192876544
author Jiang, Yonghou
Tian, Baoping
Saifuddin, Mohammed
Agy, Michael B
Emau, Peter
Cairns, J Scott
Tsai, Che-Chung
author_facet Jiang, Yonghou
Tian, Baoping
Saifuddin, Mohammed
Agy, Michael B
Emau, Peter
Cairns, J Scott
Tsai, Che-Chung
author_sort Jiang, Yonghou
collection PubMed
description BACKGROUND: Non-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 SIV(mac239 )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). RESULTS: RT-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 TCID(50 )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. CONCLUSION: This 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.
format Text
id pubmed-2780452
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-27804522009-11-21 RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models Jiang, Yonghou Tian, Baoping Saifuddin, Mohammed Agy, Michael B Emau, Peter Cairns, J Scott Tsai, Che-Chung AIDS Res Ther Research BACKGROUND: Non-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 SIV(mac239 )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). RESULTS: RT-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 TCID(50 )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. CONCLUSION: This 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. BioMed Central 2009-11-05 /pmc/articles/PMC2780452/ /pubmed/19891783 http://dx.doi.org/10.1186/1742-6405-6-23 Text en Copyright ©2009 Jiang et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Jiang, Yonghou
Tian, Baoping
Saifuddin, Mohammed
Agy, Michael B
Emau, Peter
Cairns, J Scott
Tsai, Che-Chung
RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title_full RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title_fullStr RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title_full_unstemmed RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title_short RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models
title_sort rt-shiv, an infectious ccr5-tropic chimeric virus suitable for evaluating hiv reverse transcriptase inhibitors in macaque models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780452/
https://www.ncbi.nlm.nih.gov/pubmed/19891783
http://dx.doi.org/10.1186/1742-6405-6-23
work_keys_str_mv AT jiangyonghou rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT tianbaoping rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT saifuddinmohammed rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT agymichaelb rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT emaupeter rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT cairnsjscott rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels
AT tsaichechung rtshivaninfectiousccr5tropicchimericvirussuitableforevaluatinghivreversetranscriptaseinhibitorsinmacaquemodels