Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity
Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity
复制标题
抗逆转录病毒治疗失败后的不一致结果与人类免疫缺陷病毒特异性细胞免疫的显着差异相关
作者：
D. Price;G. Scullard;A. Oxenius;R. Braganza;S. Beddows;S. Kazmi;J. Clarke;Gabriele E Johnson;J. Weber;R. Phillips
摘要许多慢性感染人类免疫缺陷病毒1型（HIV-1）的个体在连续联合抗逆转录病毒治疗（ART）期间由于出现耐药病毒或依从性差而经历血浆病毒复发。在大多数情况下，抗逆转录病毒治疗的病毒学失败与CD 4 + T淋巴细胞水平的同时下降有关。然而，尽管病毒学失败，一部分不一致的个体仍保持稳定甚至增加的CD 4 + T淋巴细胞计数。为了解决这些不同的结果的性质，我们评估了病毒学和免疫学变量在一个前瞻性的，单盲的，非随机队列的53例慢性HIV-1感染者已连续ART治疗，并在19个月内集中监测。在所有接受抗逆转录病毒治疗的可检测到病毒血症的个体中，在循环血浆病毒的pol基因中检测到对病毒生长动力学具有相似影响的多种耐药突变。此外，C2 V3 env基因分析表明，在大多数可检测到血浆病毒血症的患者中，序列指示CCR 5辅助受体的使用。与这种同质的病毒学模式相反，用一系列来自HIV-1的抗原进行的全面筛查显示出实质性的免疫学差异。在复发病毒存在下，CD 4 + T淋巴细胞计数稳定的不一致受试者表现出强效的病毒特异性CD 4+和CD 8 + T淋巴细胞应答。相反，与CD 4 + T淋巴细胞计数下降相关的病毒学失败的受试者的HIV特异性CD 4 + T淋巴细胞应答明显较弱，并表现出HIV特异性CD 8 + T淋巴细胞应答较弱的趋势。重要的是，CD 4+反应持续长达11个月，证实了这种现象的稳定性。这些相关的数据导致了可检验的假设，即在连续ART期间病毒复发的后果受到HIV特异性细胞免疫应答的调节。
ABSTRACT Many individuals chronically infected with human immunodeficiency virus type 1 (HIV-1) experience a recrudescence of plasma virus during continuous combination antiretroviral therapy (ART) due either to the emergence of drug-resistant viruses or to poor compliance. In most cases, virologic failure on ART is associated with a coincident decline in CD4+ T lymphocyte levels. However, a proportion of discordant individuals retain a stable or even increasing CD4+ T lymphocyte count despite virological failure. In order to address the nature of these different outcomes, we evaluated virologic and immunologic variables in a prospective, single-blinded, nonrandomized cohort of 53 subjects with chronic HIV-1 infection who had been treated with continuous ART and monitored intensively over a period of 19 months. In all individuals with detectable viremia on ART, multiple drug resistance mutations with similar impacts on viral growth kinetics were detected in the pol gene of circulating plasma virus. Further, C2V3 env gene analysis demonstrated sequences indicative of CCR5 coreceptor usage in the majority of those with detectable plasma viremia. In contrast to this homogeneous virologic pattern, comprehensive screening with a range of antigens derived from HIV-1 revealed substantial immunologic differences. Discordant subjects with stable CD4+ T lymphocyte counts in the presence of recrudescent virus demonstrated potent virus-specific CD4+ and CD8+ T lymphocyte responses. In contrast, subjects with virologic failure associated with declining CD4+ T lymphocyte counts had substantially weaker HIV-specific CD4+ T lymphocyte responses and exhibited a trend towards weaker HIV-specific CD8+ T lymphocyte responses. Importantly the CD4+ response was sustained over periods as long as 11 months, confirming the stability of the phenomenon. These correlative data lead to the testable hypothesis that the consequences of viral recrudescence during continuous ART are modulated by the HIV-specific cellular immune response.
影响因子：
56.9
作者：
Rosenberg, ES;Billingsley, JM;Walker, BD
通讯作者：
Walker, BD
影响因子：
56.9
作者：
Wong, JK;Hezareh, M;Richman, DD
通讯作者：
Richman, DD
影响因子：
56.9
作者：
Finzi, D;Hermankova, M;Siliciano, RF
通讯作者：
Siliciano, RF