TISSUE RESERVOIRS IN SIV-INFECTED LONG TERM NONPROGRESSORS

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 我们以前开发了一种SIV感染的中国恒河猴（ChRM）模型，用于HIV感染的长期非进展者（LTNP）。通过使用该模型，我们还证明了胃肠道，特别是结肠，是LTNP的主要储存库，即使血浆病毒载量通过标准测定法检测不到。我们正在使用这个模型来进一步验证这一假设，即SIV感染的ChRM是一个比其他非人灵长类动物更好的模型，用于研究抗逆转录病毒治疗的组织储库，用于评估病毒根除和免疫恢复的新策略。目前，我们正在对慢性SIV感染的ChRM进行抗逆转录病毒治疗（ART）。动物每天用PMPA/FTC和L-870812处理2个月。结果显示，ART治疗后血浆病毒载量降至30拷贝/ml，肠道T细胞免疫活化在ART治疗后第1个月降低，空肠和结肠黏膜记忆性CCR 5 + CD 4 + T细胞显著增加，且两者在治疗期间呈正相关。此外，这些细胞的恢复与免疫激活呈负相关。我们的研究表明，联合ART可有效抑制病毒复制，减少免疫激活，并有利于肠道免疫恢复。如果可以进一步减少肠粘膜中的残留病毒复制和储库，则将评估进一步添加蛋白酶抑制剂或其他新方案。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have previously developed a SIV-infected Chinese rhesus macaque (ChRM) model for HIV-infected long-term nonprogressors (LTNP). By using this model, we have also demonstrated that the gastrointestinal tract, especially the colon, is a major reservoir for LTNP even when plasma viral load is undetectable by standard assay. We are using this model to further test the hypothesis that ChRM of SIV infection is a better model than other nonhuman primates for studies of tissue reservoirs on antiretroviral therapy, for evaluation of new strategies of viral eradication and immune restoration. Currently, we are conducting antiretroviral therapy (ART) in chronically SIV-infected ChRM. Animals were treated with PMPA/FTC and L-870812 daily for 2 months. Our results showed that plasma viral loads were reduced to 30 copies/ml in animals receiving ART. Immune activation of T cells in the gut was reduced in the first month of ART. Both jejunal and colonic mucosal memory CCR5+CD4+ T cells increased significantly and they were positively correlated during treatment. Moreover, restoration of these cells was inversely correlated with immune activation. Our studies indicate that combination ART is effective to suppress viral replication, reduce immune activation, and benefit to immune restoration in the gut. Further addition of protease inhibitors or other new regimens are to be evaluated if further reduction of residual viral replication and reservoir can be achieved in the intestinal mucosa.