aInserm UMR S-943 bVirology Department cInfectious Disease Department dInternal Medicine Department, Pitie-Salpetriere Hospital eUniversité Pierre and Marie Curie fInserm UMR S945 gAP-HP hImmunology Department, Pitie-Salpetriere Hospital, Paris, France.
AIDS. 2014 Feb 20;28(4):487-91. doi: 10.1097/QAD.0000000000000182.
Previous studies on HIV quasispecies have revealed HIV compartmentalization in various tissues within an infected individual. Such HIV variation is a result of a combination of factors including high replication and mutation rates, recombination, and APOBEC3-host selective pressure.
To evaluate the differential impact of APOBEC3 editing in HIV-1 compartments, we analyzed the level of G-to-A hypermutation in HIV-1 protease and reverse transcriptase sequences among 30 HAART-treated patients for whom peripheral blood mononuclear cells and body tissues or fluids [cerebral spinal fluid (CSF), rectal tissue, or renal tissue] were collected on the same day.
APOBEC3-mediated hypermutation was identified in 36% (11/30) of participants in at least one viral reservoir. HIV hypermutated sequences were often observed in viral sanctuaries (total n = 10; CSF, n = 6; renal tissue, n = 1; rectal tissue n = 3) compared with peripheral blood (total n = 4). Accordingly, APOBEC3 editing generated more G-to-A drug resistance mutations in sanctuaries: three patients' CSF (i.e. G73S in protease; M184I, M230I in reverse transcriptase) and two other patients' rectal tissues (M184I, M230I in reverse transcriptase) while such mutations were absent from paired peripheral blood mononuclear cells.
APOBEC3-induced mutations observed in peripheral blood underestimate the overall proportion of hypermutated viruses in anatomical compartments. The resulting mutations may favor escape to antiretrovirals in these compartments in conjunction with a lower penetration of drugs in some sanctuaries. On the other side, because hypermutated sequences often harbor inactivating mutations, our results suggest that accumulation of defective viruses may be more dominant in sanctuaries than in peripheral blood of patients on effective HAART.
先前关于 HIV 准种的研究揭示了感染个体体内各种组织内的 HIV 分隔现象。这种 HIV 变异是多种因素共同作用的结果，包括高复制和突变率、重组以及 APOBEC3 与宿主的选择性压力。
为了评估 APOBEC3 在 HIV-1 区室中的编辑作用的差异影响，我们分析了 30 位接受 HAART 治疗的患者中 HIV-1 蛋白酶和逆转录酶序列的 G 到 A 超突变水平，这些患者在同一天采集了外周血单核细胞和身体组织或体液（脑脊液[CSF]、直肠组织或肾组织）。
在至少一个病毒储存库中，有 36%（11/30）的参与者存在 APOBEC3 介导的超突变。与外周血（总 n = 4）相比，超突变序列经常在病毒避难所中观察到（总 n = 10；CSF，n = 6；肾组织，n = 1；直肠组织 n = 3）。因此，APOBEC3 编辑在避难所中产生了更多的 G 到 A 耐药突变：三位患者的 CSF（即蛋白酶中的 G73S；逆转录酶中的 M184I、M230I）和另外两位患者的直肠组织（逆转录酶中的 M184I、M230I），而这些突变在配对的外周血单核细胞中不存在。
在外周血中观察到的 APOBEC3 诱导的突变低估了解剖区室中高度突变病毒的总体比例。由此产生的突变可能与某些避难所中药物渗透较低相结合，有利于这些区室中抗逆转录病毒的逃逸。另一方面，由于超突变序列通常含有失活突变，我们的结果表明，在有效接受 HAART 的患者的避难所中，缺陷病毒的积累可能比在外周血中更为普遍。
