Yanqin Ren1, Liangzhu Li, Yanmin Wan, Wei Wang, Jing Wang, Jian Chen, Qiang Wei, Chuan Qin, Jianqing Xu, Xiaoyan Zhang. 1. *Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College of Fudan University, Shanghai, China; †Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China; and ‡Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine; Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, Beijing, China.
Abstract
OBJECTIVE: To determine whether mucosal topical microbicides have any influence on disease progression during subsequent simian immunodeficiency virus (SIV) infection. DESIGN: A 2-phase study was performed in primate monkeys. The first phase mimicked microbicide efficacy studies; the second phase served to determine the disease progression in a productive infection model. METHODS: During the first phase, monkeys were intrarectally pretreated with tenofovir, sifuvirtide (SFT), or maraviroc-formulated microbicides and then challenged with low-dose SHIV-1157ipd3N4. Second, all monkeys were rechallenged with a single high dose of SIVmac239 to generate productive infections. The survival rate, viral loads, CD4(+) T-cell counts, and SIV-specific T-cell responses were determined during the 104-week following up. RESULTS: Repeated rectal challenges did not result in productive infection in all groups, evidenced by undetectable viral loads with occasional viral blips during the first phase of this study. All monkeys were productively infected after the high-dose rechallenge with SIVmac239. Two groups, including maraviroc-treated and tenofovir-treated groups, experienced 100% mortality during the 104-week following up. In contrast, the SFT-treated group showed significantly higher survival, and only 25% died at week 95. Interestingly, SIV-specific T-cell responses were also significantly higher in the SFT group. Transcriptomic analyses evidenced immune imprint in immune system among different microbicide-treated groups. CONCLUSIONS: This study provides preliminary but important evidence for the influence of prophylactically applied microbicides on disease progression of subsequent SIV infection and suggests that the long-term immune safety concern for microbicides should be also considered in the effort to develop effective microbicides.
OBJECTIVE: To determine whether mucosal topical microbicides have any influence on disease progression during subsequent simian immunodeficiency virus (SIV) infection. DESIGN: A 2-phase study was performed in primate monkeys. The first phase mimicked microbicide efficacy studies; the second phase served to determine the disease progression in a productive infection model. METHODS: During the first phase, monkeys were intrarectally pretreated with tenofovir, sifuvirtide (SFT), or maraviroc-formulated microbicides and then challenged with low-dose SHIV-1157ipd3N4. Second, all monkeys were rechallenged with a single high dose of SIVmac239 to generate productive infections. The survival rate, viral loads, CD4(+) T-cell counts, and SIV-specific T-cell responses were determined during the 104-week following up. RESULTS: Repeated rectal challenges did not result in productive infection in all groups, evidenced by undetectable viral loads with occasional viral blips during the first phase of this study. All monkeys were productively infected after the high-dose rechallenge with SIVmac239. Two groups, including maraviroc-treated and tenofovir-treated groups, experienced 100% mortality during the 104-week following up. In contrast, the SFT-treated group showed significantly higher survival, and only 25% died at week 95. Interestingly, SIV-specific T-cell responses were also significantly higher in the SFT group. Transcriptomic analyses evidenced immune imprint in immune system among different microbicide-treated groups. CONCLUSIONS: This study provides preliminary but important evidence for the influence of prophylactically applied microbicides on disease progression of subsequent SIV infection and suggests that the long-term immune safety concern for microbicides should be also considered in the effort to develop effective microbicides.