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Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques(Macaca leonina)

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Zoological Research 2016年第4期37卷 246-251页

作者： Xiao-Liang ZHANG Jia-Hao SONG Wei PANG Yong-Tang ZHENG Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Faculty of Life Science and Technology Kunming University of Science and Technology Institute of Health Sciences Anhui University Kunming Primate Research Center of the Chinese Academy of Sciences Kunming Institute of Zoology Chinese Academy of Sciences

Northern pig-tailed macaques （NPMs, Macaca leonina） are susceptible to HIV-1 infection largely due to the loss of HIV-l-restricting factor TRIM5a. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences （CDSs） showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection.

关键词： Macaca leonina Northern pig-tailed macaques APOBEC3 HIV-1

Superior intestinal integrity and limited microbial translocation are associated with lower immune activation in SIVmac239-infected northern pig-tailed macaques(Macaca leonina)

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Zoological Research 2019年第6期40卷 522-531页

作者： Ming-Xu Zhang Tian-Zhang Song Hong-Yi Zheng Xue-Hui Wang Ying Lu Han-Dan Zhang Ting Li Wei Pang Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province National Kunming High Level Biosafety Research Center for Non-human PrimatesKIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunming Yunnan 650223China Kunming College of Life Science University of Chinese Academy of SciencesKunming Yunnan 650204China School of Life Sciences University of Science and Technology of ChinaHefei Anhui 230026China KIZ-SU Joint Laboratory of Animal Models and Drug Development College of Pharmaceutical SciencesSoochow UniversitySuzhou Jiangsu 215123China

Microbial translocation is a cause of systemic immune activation in HIV/SIV infection. In the present study, we found a lower CD8+ T cell activation level in Macaca leonina (northern pig-tailed macaques, NPMs) than in Macaca mulatta (Chinese rhesus macaques, ChRMs) during SIVmac239 infection. Furthermore, the levels of plasma LPS-binding protein and soluble CD14 in NPMs were lower than those in ChRMs. Compared with ChRMs, SIV-infected NPMs had lower Chiu scores, representing relatively normal intestinal mucosa. In addition, no obvious damage to the ileum or colon epithelial barrier was observed in either infected or uninfected NPMs, which differed to that found in ChRMs. Furthermore, no significant microbial translocation (Escherichia coli) was detected in the colon or ileum of infected or uninfected NPMs, which again differed to that observed in ChRMs. In conclusion, NPMs retained superior intestinal integrity and limited microbial translocation during SIV infection, which may contribute to their lower immune activation compared with ChRMs.

关键词： Immune activation Intestinal integrity Microbial translocation SIVmac239 Macaca leonina Northern pig-tailed macaques Macaca mulatta Chinese rhesus macaques

Parasites may exit immunocompromised northern pig-tailed macaques (Macaca leonina)infected with SIVmac239

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Zoological Research 2018年第1期39卷 42-51页

作者： tian-zhang song ming-xu zhang yu-jie xia yu xiao wei pang yong-tang zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Kunming Institute of ZoologyChinese Academy of SciencesKunming Yunnan 650223China University of Chinese Academy of Sciences Bejing 100049China Kunming Primate Research Center Kunming Institute of ZoologyChinese Academy of SciencesKunming Yunnan 650223China

Parasites can increase infection rates and pathogenicity in immunocompromised human immunodeficiency virus （HIV） patients. However, in vitro studies and epidemiological investigations also suggest that parasites might escape immunocompromised hosts during HIV infection Due to the lack of direct evidence from animal experiments, the effects of immunocompromised hosts parasitic infections on remain unclear. Here we detected 14 different parasites in six northern pig-tailed macaques （NPMs） before or at the 50th week of simian immunodeficiency virus （SIV） infection by ELISA. The NPMs all carried parasites before viral injection. At the 50th week after viral injection, the individuals with negative results in parasitic detection （i.e., 08247 and 08287） were characterized as the Parasites Exit （PE） group, with the other individuals （i.e., 09203, 09211, 10205, and 10225） characterized as the Parasites Remain （PR） group. Compared with the PR group, the NPMs in the PE group showed higher viral loads, lower CD4＋ T cells counts, and lower CD4/CD8 rates. Additionally, the PE group had higher immune activation and immune exhaustion of both CD4~ and CD8~ T cells. Pathological observation showed greater injury to the liver, cecum, colon, spleen, and mesenteric lymph nodes in the PE group This study showed more seriously compromised immunity in the PE group, strongly indicating that parasites might exit an immunocompromised host.

关键词： AIDS Immunocompromised Northernpig-tailed macaque Parasite SIVmac239

Association of TRIMCyp and TRIM5α from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition

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Science China(Life Sciences) 2018年第8期61卷 954-965页

作者： Dan Mu Jia-Wu Zhu Feng-Liang Liu Hong-Yi Zheng Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming 650223 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming 650204 China Kunming Primate Research Center Chinese Academy of Sciences Kunming 650223 China

TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A(TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera(am TRIMCyp), along with a TRIM5α allelic protein(am TRIM5α). Herein,we investigated the antiviral activity of am TRIMCyp and am TRIM5α individually, as well as their interaction and joint *** TRIMCyp showed a divergent restriction pattern from am TRIM5α. Although both proteins potently restricted the replication of HIV-1, only am TRIM5α inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when am TRIMCyp and am TRIM5α were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous am TRIM5α/TRIMCyp showed stronger resistance to HIV-1 infection than those from am TRIM5α/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the am TRIMCyp-am TRIM5α interaction. In contrast, am TRIMCyp completely abrogated the anti-N-MLVactivity mediated by am TRIM5α, showing a dominant-negative effect, indicating that the generation of am TRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies.

关键词： HIV-1 交易猕猴协会相互作用蛋白质学习功能动物模型

HIV-1 can infect northern pig-tailed macaques(Macaca leonina) and form viral reservoirs in vivo

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Science Bulletin 2017年第19期62卷 1315-1324页

作者： Wei Pang Gao-Hong Zhang Jin Jiang Hong-Yi Zheng Lin-Tao Zhang Xiao-Liang Zhang Jia-Hao Song Ming-Xu Zhang Jia-Wu Zhu Ai-Hua Lei Ren-Rong Tian Xiao-Ming Liu Liguo Zhang Guangxia Gao Lishan Su Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Kunming Institute of ZoologyChinese Academy of Sciences University of Chinese Academy of Sciences Institute of Health Sciences Anhui University South China Institute of Endangered Animal Guandong Academy of Sciences Key Laboratory of Infection and Immunity Institute of BiophysicsChinese Academy of Sciences Department of Microbiology and Immunology School of MedicineThe University of North Carolina at Chapel Hill

Viral reservoirs of HIV-1 are a major obstacle for curing AIDS. The novel animal models that can be directly infected with HIV-1 will contribute to develop effective strategies for eradicating ***, we inoculated 4 northern pig-tailed macaques(NPM) with the HIV-1 strain HIV-1_(NL4.3) and monitored the infection for approximately 3 years(150 weeks). The HIV-1-infected NPMs showed transient viremia for about 10 weeks after infection. However, cell-associated proviral DNA and viral RNA persisted in the peripheral blood and lymphoid organs for about 3 years. Moreover, replication-competent HIV-1could be successfully recovered from peripheral blood mononuclear cells(PBMCs) during long-term infection. The numbers of resting CD4^+T cells in HIV-1 infected NPMs harboring proviruses fell within a range of 2-to 3-log_(10) per million cells, and these proviruses could be reactivated both ex vivo and in vivo in response to co-stimulation with the latency-reversing agents JQ1 and prostratin. Our results suggested that NPMs can be infected with HIV-1 and a long-term viral reservoir was formed in NPMs,which might serve as a potential model for HIV-1 reservoir research.

关键词： HIV-1 病毒库感染外周血单个核细胞猕猴体内北方猪

葡萄糖代谢异常导致SIVmac239感染北平顶猴急性期体重变化

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中国实验动物学报 2018年第6期26卷 693-699页

作者：张瀚丹宋天章杨柳萌郑永唐大理大学药学与化学学院云南大理671000 中国科学院昆明动物研究所、云南省活性多肽研究与利用重点实验室/中国科学院动物模型与人类疾病重点实验室国家昆明高等级生物安全灵长类动物实验中心昆明650223

目的探讨艾滋病急性期炎症因子、脂类代谢及葡萄糖代谢对体重的影响。方法检测SIVmac239感染北平顶猴急性期炎症因子(TNF-α、IL-6)、脂类代谢(胆固醇、三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇)及葡萄糖代谢参数(胰岛素、胰... 详细信息

目的探讨艾滋病急性期炎症因子、脂类代谢及葡萄糖代谢对体重的影响。方法检测SIVmac239感染北平顶猴急性期炎症因子(TNF-α、IL-6)、脂类代谢(胆固醇、三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇)及葡萄糖代谢参数(胰岛素、胰岛素抵抗指数),比较体重增加组和体重减少组SIV感染北平顶猴之间的差异,运用Pearson相关分析探讨胰岛素抵抗与血浆病毒载量的相关性。结果在SIVmac239感染北平顶猴急性期,炎症因子和血脂四项在体重增加组与体重减少组之间无明显差异;体重增加组胰岛素水平明显下降,体重减少组胰岛素水平明显升高,并出现胰岛素抵抗表现;Pearson分析显示,感染后第5周及第11周胰岛素抵抗指数变化与血浆病毒载量呈正相关。结论 SIVmac239感染急性期,葡萄糖代谢异常可能是导致北平顶猴体重变化的主要原因。

关键词：艾滋病 SIVmac239 北平顶猴体重胰岛素抵抗

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氯喹/羟氨喹在艾滋病治疗中的应用研究进展

国际药学研究杂志 2017年第1期44卷 13-17页

作者：向思颖张高红郑永唐昆明医科大学药学院暨云南省天然药物药理重点实验室昆明650500 中国科学院昆明动物研究所.中国科学院和云南省动物模型与人类疾病机理重点实验室昆明650223

联合抗逆转录疗法(c ART)能有效抑制HIV复制和增加CD4+细胞数量,但对HIV引起的免疫活化则无明显抑制作用,持续免疫活化目前已经成为治疗AIDS的一大难题。氯喹/羟氯喹具有免疫调节功能,能抑制浆细胞样树突状细胞(p DC)活化进而有效降低... 详细信息

联合抗逆转录疗法(c ART)能有效抑制HIV复制和增加CD4+细胞数量,但对HIV引起的免疫活化则无明显抑制作用,持续免疫活化目前已经成为治疗AIDS的一大难题。氯喹/羟氯喹具有免疫调节功能,能抑制浆细胞样树突状细胞(p DC)活化进而有效降低免疫活化水平。此外,氯喹/羟氯喹还可通过干扰HIV包膜糖蛋白gp120糖基化抑制病毒复制及通过抑制记忆性T细胞自噬而诱导其凋亡,安全性高、毒性低,可作为一种辅助治疗药物用于HIV治疗。

关键词：氯喹羟氯喹 HIV 免疫活化