Hermankova M, Ray S C, Ruff C, Powell-Davis M, Ingersoll R, D'Aquila R T, Quinn T C, Siliciano J D, Siliciano R F, Persaud D
Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N Wolfe St, 256 Park Bldg, Baltimore, MD 21287, USA.
JAMA. 2001 Jul 11;286(2):196-207. doi: 10.1001/jama.286.2.196.
The continued release of human immunodeficiency virus type 1 (HIV-1) into plasma at very low levels during highly active antiretroviral therapy (HAART) can be detected using specialized techniques, but the nature and significance of this low-level viremia, especially as related to acquisition of drug resistance mutations, are unclear.
To determine genetic resistance profiles of low-level plasma HIV-1 in patients with prolonged viral suppression (<50 copies/mL of plasma HIV-1 RNA) while receiving HAART.
Cross-sectional study conducted at a US academic hospital from November 1999 to February 2001 using a novel method for amplification of low levels of viral genomes in plasma.
Eighteen HIV-1-infected patients (7 children and 11 adults), enrolled in a longitudinal study of HIV-1 reservoirs, who had suppression of viral replication while receiving protease inhibitor-containing combination therapy. Two patients (1 adult and 1 child) with less optimal suppression of viral replication were included to assess virus predominating when plasma HIV-1 RNA levels are low but detectable (<1000 copies/mL). Follow-up analyses were conducted in 3 patients.
Detection of drug resistance mutations in clones amplified from low-level plasma virus.
Viral sequences were amplified from 8 of the 18 patients with simultaneous plasma HIV-1 measurements of less than 50 copies/mL and from 2 patients with 231 and 50 copies/mL. Clones from 3 treatment-naive patients with less than 50 copies/mL of plasma HIV-1 RNA showed continued release, for as long as 42 months, of wild-type drug-sensitive virus. The 7 patients with prior nonsuppressive therapy, with viral loads below 50 copies/mL and during "blips" to 231 and 64 copies/mL, had only resistance mutations consistent with pre-HAART therapy (although reverse transcriptase inhibitor mutations may have continued to occur). New HAART-related mutations were seen in a control patient with prior viral load levels of about 400 to 1000 copies/mL. For phylogenetic analysis, sequences were available for both resting CD4(+) T cells and plasma HIV for 7 of 10 patients and showed patient-specific clustering of sequences and a close relationship between virus in the plasma and the latent reservoir.
Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia to less than 50 copies/mL of HIV-1 RNA may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART-selected mutations reflecting partial resistance to therapy. Low-level viremia below 50 copies/mL may represent less of a concern regarding impending drug failure of current HAART regimens. However, the archival drug-resistant virus may be relevant regarding future treatment strategies.
在高效抗逆转录病毒治疗（HAART）期间，可使用专门技术检测到人类免疫缺陷病毒1型（HIV-1）以极低水平持续释放到血浆中，但这种低水平病毒血症的性质和意义尚不清楚，尤其是与获得耐药突变的关系。
确定接受HAART治疗且病毒长期抑制（血浆HIV-1 RNA<50拷贝/mL）的患者中血浆低水平HIV-1的基因耐药谱。
1999年11月至2001年2月在美国一家学术医院进行的横断面研究，采用一种新方法扩增血浆中低水平的病毒基因组。
18例HIV-1感染患者（7名儿童和11名成人），参与HIV-1储存库的纵向研究，在接受含蛋白酶抑制剂的联合治疗期间病毒复制受到抑制。纳入2例病毒复制抑制不太理想的患者（1名成人和1名儿童），以评估血浆HIV-1 RNA水平低但可检测到（<1000拷贝/mL）时占主导地位的病毒。对3例患者进行了随访分析。
从低水平血浆病毒扩增的克隆中检测耐药突变。
在18例患者中有8例同时检测到血浆HIV-1低于50拷贝/mL时扩增出病毒序列，另外2例患者血浆HIV-1分别为231拷贝/mL和50拷贝/mL时也扩增出病毒序列。3例未经治疗的患者血浆HIV-1 RNA低于50拷贝/mL，其克隆显示野生型药物敏感病毒持续释放长达42个月。7例先前治疗未达抑制效果的患者，病毒载量低于50拷贝/mL，在“病毒波动”至231拷贝/mL和64拷贝/mL期间，仅出现与HAART治疗前一致的耐药突变（尽管逆转录酶抑制剂突变可能仍在发生）。1例先前病毒载量约为400至1000拷贝/mL的对照患者出现了新的HAART相关突变。为进行系统发育分析，10例患者中有7例可获得静息CD4(+)T细胞和血浆HIV的序列，结果显示序列存在患者特异性聚类，且血浆中的病毒与潜伏储存库中的病毒关系密切。
基于能够扩增的样本，接受HAART治疗且病毒血症长期抑制至HIV-1 RNA低于50拷贝/mL的儿童和成人中的低水平病毒血症可能主要源于存档的HAART治疗前病毒，反映了早期治疗情况，似乎不需要产生反映对治疗部分耐药的新的HAART选择突变。低于50拷贝/mL的低水平病毒血症可能对当前HAART方案即将出现的治疗失败影响较小。然而，存档的耐药病毒可能与未来的治疗策略相关。
