Kostrikis Leondios G, Touloumi Giota, Karanicolas Rose, Pantazis Nikos, Anastassopoulou Cleo, Karafoulidou Anastasia, Goedert James J, Hatzakis Angelos
Department of Hygiene and Epidemiology, Athens University Medical School, 75 Mikras Asias, 11527 Athens, Greece.
J Virol. 2002 Oct;76(20):10099-108. doi: 10.1128/jvi.76.20.10099-10108.2002.
There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 10(6) PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval (CI), 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 10(6) PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.
在未经治疗的HIV-1感染个体以及血浆HIV-1 RNA水平通过长期联合抗逆转录病毒疗法得到抑制的患者的外周血T细胞和淋巴结中，存在几种形式的1型人类免疫缺陷病毒（HIV-1）DNA。然而，细胞中HIV-1 DNA的浓度是否能预测HIV-1感染的临床结局仍有待确定。在本报告中，我们测量了外周血单核细胞（PBMC）样本中经历了第二次模板转换的HIV-1 DNA形式（STS DNA）和2-长末端重复DNA环的浓度。为此，我们使用基于分子信标的实时PCR检测方法，并在多中心血友病队列研究中对130例血友病患者进行了研究。我们通过Kaplan-Meier和Cox回归分析评估了在未进行联合抗逆转录病毒治疗的情况下，基线HIV-1 STS DNA水平对HIV-1疾病进展的影响。在进展为艾滋病的患者中，PBMC中STS HIV-1 DNA的中位数水平（四分位间距）显著高于在16年随访期间未患艾滋病的患者（分别为每10(6)个PBMC中1,017 [235至6,059]和286 [31至732]拷贝；P < 0.0001）。根据HIV-1 STS DNA水平的四分位数分布，进展为死亡和艾滋病的发生率差异显著（对数秩检验P < 0.001）。在调整了血清转化时的年龄、基线CD4(+) T细胞计数、血浆病毒载量和T细胞受体切除环后，HIV-1 STS DNA水平越高，死亡和艾滋病的相对风险（RH）显著增加（每10(6)个PBMC每增加10倍，调整后的RH分别为1.84 [95%置信区间（CI），1.30至2.59]和2.62 [95% CI，1.75至3.93]）。在16年的随访期间，每个个体的HIV-1 STS DNA水平在纵向PBMC样本中保持稳定。我们的研究结果表明，PBMC中HIV-1 STS DNA的浓度在预测HIV-1疾病的临床结局方面补充了血浆中的HIV-1 RNA载量。该参数可能对理解联合抗逆转录病毒治疗的病毒学反应具有重要意义。
