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首页> 美国卫生研究院文献>Journal of Virology >Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity
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Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity

机译：抗逆转录病毒疗法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实质性差异相关

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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.
机译：由于抗药性病毒的出现或依从性差，许多长期感染1型人类免疫缺陷病毒（HIV-1）的个体在连续联合抗逆转录病毒治疗（ART）期间经历了血浆病毒的复发。在大多数情况下，ART的病毒学衰竭与CD4 + T淋巴细胞水平的同时下降有关。然而，尽管有病毒学上的失败，一部分不和谐的个体仍保持稳定甚至增加的CD4 + T淋巴细胞计数。为了解决这些不同结果的本质，我们评估了53名慢性HIV-1感染者的前瞻性，单盲，非随机队列中的病毒学和免疫学变量，这些受试者接受了连续抗逆转录病毒治疗并在一段时间内进行了严格监测19个月。在ART中可检测到病毒血症的所有个体中，在循环血浆病毒的pol基因中检测到多种对病毒生长动力学具有相似影响的耐药性突变。此外，C2V3 env基因分析证明了在大多数可检出血浆病毒血症的患者中，指示CCR5共受体使用的序列。与这种均质的病毒学模式相反，使用一系列源自HIV-1的抗原进行全面筛选显示出实质性的免疫学差异。在复发性病毒存在下，CD4 + T淋巴细胞计数稳定的不一致受试者表现出强力的病毒特异性CD4 + 和CD8 + T淋巴细胞反应。相反，与CD4 + T淋巴细胞计数下降相关的病毒学衰竭受试者的HIV特异性CD4 + T淋巴细胞反应明显减弱，并且呈现出HIV特异性CD8减弱的趋势 + T淋巴细胞反应。重要的是，CD4 + 反应持续了长达11个月的时间，证实了这一现象的稳定性。这些相关数据导致了可验证的假设，即在连续抗病毒治疗期间病毒再发的后果受到HIV特异性细胞免疫反应的调节。

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