Replication-Competent Simian Immunodeficiency Virus (SIV) Gag Escape Mutations Archived in Latent Reservoirs during Antiretroviral Treatment of SIV-Infected Macaques
Replication-Competent Simian Immunodeficiency Virus (SIV) Gag Escape Mutations Archived in Latent Reservoirs during Antiretroviral Treatment of SIV-Infected Macaques
复制标题
具有复制能力的猿猴免疫缺陷病毒 (SIV) Gag 逃逸突变在感染 SIV 的猕猴抗逆转录病毒治疗期间存档在潜伏储库中
作者：
S. Queen;Brian M Mears;K. Kelly;Jamie L. Dorsey;Z. Liao;J. Dinoso;L. Gama;R. Adams;M. Zink;J. Clements;S. Kent;J. Mankowski
人类免疫缺陷病毒（HIV）逃避主要组织相容性复合体（MHC）I类基因介导的CD8+ T细胞控制的压力，常常在MHC I类基因识别的免疫显性表位上发生突变。虽然目前对艾滋病毒感染患者的标准治疗是用高效抗逆转录病毒疗法（HAART）治疗，但这些患者中病毒复制的抑制不是绝对的，潜伏感染的细胞作为终身储存库持续存在。为了确定在HAART治疗期间HIV是否从MHC I类限制性CD8+ T细胞控制中逃逸，然后进入外周和中枢神经系统（CNS）的潜伏储库，并有可能成为具有复制能力的病毒，我们跟踪了HAART治疗的猴免疫缺陷病毒（SIV）Gag逃逸突变K165 R的纵向发展。这些研究的主要结果包括：（i）在抑制病毒复制之前，在HAART启动后病毒血症的衰变阶段期间，在血浆和脑脊液（CSF）中出现SIV Gag K165R逃逸突变。（ii）SIV K165R Gag逃逸突变在潜伏的前病毒DNA储库中存档，包括接受抑制病毒复制的HAART的动物的脑，和（iii）在HAART处理的SIV感染的猕猴中，在静息的CD4+ T细胞库中存在有复制能力的SIV Gag K165R逃逸突变。尽管早期给予积极的抗逆转录病毒治疗，HIV免疫逃逸CD8+ T细胞控制仍然可以在病毒血症的衰减阶段发展，然后持续存在于潜伏的水库，包括大脑，如果HAART治疗中断，可能会出现。
ABSTRACT In response to pressure exerted by major histocompatibility complex (MHC) class I-mediated CD8+ T cell control, human immunodeficiency virus (HIV) escape mutations often arise in immunodominant epitopes recognized by MHC class I alleles. While the current standard of care for HIV-infected patients is treatment with highly active antiretroviral therapy (HAART), suppression of viral replication in these patients is not absolute and latently infected cells persist as lifelong reservoirs. To determine whether HIV escape from MHC class I-restricted CD8+ T cell control develops during HAART treatment and then enters latent reservoirs in the periphery and central nervous system (CNS), with the potential to emerge as replication-competent virus, we tracked the longitudinal development of the simian immunodeficiency virus (SIV) Gag escape mutation K165R in HAART-treated SIV-infected pigtailed macaques. Key findings of these studies included: (i) SIV Gag K165R escape mutations emerged in both plasma and cerebrospinal fluid (CSF) during the decaying phase of viremia after HAART initiation before suppression of viral replication, (ii) SIV K165R Gag escape mutations were archived in latent proviral DNA reservoirs, including the brain in animals receiving HAART that suppressed viral replication, and (iii) replication-competent SIV Gag K165R escape mutations were present in the resting CD4+ T cell reservoir in HAART-treated SIV-infected macaques. Despite early administration of aggressive antiretroviral treatment, HIV immune escape from CD8+ T cell control can still develop during the decaying phases of viremia and then persist in latent reservoirs, including the brain, with the potential to emerge if HAART therapy is interrupted.
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DOI：
10.1086/653213
发表时间：
2010-07-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Zink MC;Brice AK;Kelly KM;Queen SE;Gama L;Li M;Adams RJ;Bartizal C;Varrone J;Rabi SA;Graham DR;Tarwater PM;Mankowski JL;Clements JE
通讯作者：
Clements JE
影响因子：
--
作者：
Letendre, Scott;Marquie-Beck, Jennifer;Ellis, Ronald J.
通讯作者：
Ellis, Ronald J.
DOI：
10.1073/pnas.050567397
发表时间：
2000-03-14
影响因子：
11.1
作者：
Migueles, SA;Sabbaghian, MS;Connors, M
通讯作者：
Connors, M
DOI：
--
发表时间：
1997
期刊：
The American journal of pathology
影响因子：
--
作者：
Zink,MC;Amedee,AM;Mankowski,JL;Craig,L;Didier,P;Carter,DL;Muñoz,A;Murphey-Corb,M;Clements,JE
通讯作者：
Clements,JE
影响因子：
56.9
作者：
Wong, JK;Hezareh, M;Richman, DD
通讯作者：
Richman, DD