Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy
Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy
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DOI：
10.1056/nejm199905273402101
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发表时间：
1999-05-27
影响因子：
158.5
通讯作者：
Ho, DD
中科院分区：
文献类型：
--
作者：
Zhang, LQ;Ramratnam, B;Ho, DD
背景 对于感染 1 型人类免疫缺陷病毒 (HIV-1) 的患者，联合抗逆转录病毒治疗可持续抑制血浆病毒水平。然而，仍然可以从潜伏感染的静息记忆CD4淋巴细胞中回收具有复制能力的病毒；这一发现引起了人们对抗病毒治疗是否能够根除HIV-1的严重怀疑。 方法我们在八名患者中寻找残留HIV-1复制的证据，这些患者在感染后不久就开始治疗，并且在抗逆转录病毒治疗两到三年后血浆中HIV-1 RNA水平检测不到。我们检查了外周血单核鳗鱼中的 HIV-1 前病毒序列是否随时间发生变化，这表明残留的病毒复制。我们还对一名患者的组织进行了原位杂交研究，以鉴定积极表达 HIV-1 RNA 的细胞。我们根据初次感染期间鉴定的原病毒序列数量的减少以及对潜伏病毒库大小的直接连续测量，估计了静息 CD4 淋巴细胞中潜伏的、具有复制能力的 HIV-1 的减少率。结果 8 名患者中的 6 名在治疗期间前病毒序列没有显着变化。然而，在两名患者中存在序列进化，但没有耐药病毒基因型的证据。在一名患者中，广泛的原位研究提供了病毒在淋巴组织中持续复制的额外证据。使用两种独立的方法，我们估计静息 CD4 淋巴细胞中潜伏的、具有复制能力的病毒的半衰期约为六个月。 结论 这些发现表明，联合抗逆转录病毒疗法可抑制部分患者（但并非所有患者）的 HIV-1 复制。鉴于潜伏感染的 CD4 淋巴细胞的半衰期约为六个月，可能需要多年有效的抗逆转录病毒治疗才能消除 HIV-1 的储存库。 （N Engl J Med 1999；340：1605-13。）(C) 1999，马萨诸塞州医学会。
Background In patients infected with human immunodeficiency virus type 1 (HIV-1), combination antiretroviral therapy can result in sustained suppression of plasma levels of the virus. However, replication-competent virus can still be recovered from latently infected resting memory CD4 lymphocytes; this finding raises serious doubts about whether antiviral treatment can eradicate HIV-1.Methods We looked for evidence of residual HIV-1 replication in eight patients who began treatment soon after infection and in whom plasma levels of HIV-I RNA were undetectable after two to three years of antiretroviral therapy. We examined whether there had been changes over time in HIV-1 proviral sequences in peripheral-blood mononuclear eel Is, which would indicate residual viral replication. We also performed in situ hybridization studies on tissues from one patient to identify cells actively expressing HIV-1 RNA. We estimated the rate of decrease of latent, replication-competent HIV-1 in resting CD4 lymphocytes on the basis of the decrease in the numbers of proviral sequences identified during primary infection and direct sequential measurements of the size of the latent reservoir.Results Six of the eight patients had no significant variations in proviral sequences during treatment. However, in two patients there was sequence evolution but no evidence of drug-resistant viral genotypes. In one patient, extensive in situ studies provided additional evidence of persistent viral replication in lymphoid tissues. Using two independent approaches, we estimated that the half-life of the latent, replication-competent virus in resting CD4 lymphocytes was approximately six months.Conclusions These findings suggest that combination antiretroviral regimens suppress HIV-1 replication in some but not all patients. Given the half-life of latently infected CD4 lymphocytes of about six months, it may require many years of effective antiretroviral treatment to eliminate this reservoir of HIV-1. (N Engl J Med 1999;340:1605-13.) (C) 1999, Massachusetts Medical Society.