Wei Xierong, Lipscomb Jonathan T, Tino Ariana Santos, Cong Mian-Er, Ruone Susan, Bentz Meghan L, Sheth Mili, Garcia-Lerma Gerardo, Johnson Jeffrey A
Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
Anyar Inc., 2113 Lewis Turner Blvd, Fort Walton Beach, FL 32547, USA.
Viruses. 2024 Nov 30;16(12):1874. doi: 10.3390/v16121874.
The HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3'-polypurine tract (3'-PPT) adjacent to the 3'-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and is used in formulations for treatment and long-acting pre-exposure prophylaxis. We examined whether mutations observed for DTG would emerge in vitro with CAB. HIV-1IIIB was cultured in paired experiments of continuous high (300 nM) CAB initiated 2 h or 24 h after infection. After eight months of CAB treatment, no int resistance was detected. Conversely, HIV RNA 3'-PPT mutants were detected within one month and were the majority virus by day 98. The appearance of 3'-PPT variants coincided with a rapid accumulation of HIV 1-LTR and 2-LTR circles. RNA amplification from the 3'-LTR TAR identified transcripts crossing 2-LTR circle junctions, which incorporated the adjacent U5 sequence identical to the 3'-PPT mutants. 3'-PPT variants were only identified in LTR circles and transcripts. Additionally, we found evidence of linear HIV and LTR circle recombination with human DNA at motifs homologous to 3'-PPT sequences. HIV persistence under CAB was associated with transcription and recombination of LTR circle sequences.
据报道，在不引发整合酶（int）耐药性的情况下，HIV整合酶抑制剂多替拉韦（DTG）会在病毒3'-多聚嘌呤序列（3'-PPT）中选择靠近3'-长末端重复序列（3'-LTR）U3的突变。DTG的类似物卡博特韦（CAB）具有较高的耐药性遗传屏障，可用于治疗和长效暴露前预防制剂。我们研究了在体外使用CAB时是否会出现DTG所观察到的突变。HIV-1IIIB在感染后2小时或24小时开始的连续高剂量（300 nM）CAB配对实验中培养。经过八个月的CAB治疗，未检测到整合酶耐药性。相反，在一个月内检测到HIV RNA 3'-PPT突变体，到第98天时它们成为主要病毒。3'-PPT变体的出现与HIV 1-LTR和2-LTR环的快速积累同时发生。从3'-LTR TAR进行RNA扩增，鉴定出跨越2-LTR环连接点的转录本，这些转录本包含与3'-PPT突变体相同的相邻U5序列。3'-PPT变体仅在LTR环和转录本中被鉴定出来。此外，我们发现了线性HIV和LTR环与人类DNA在与3'-PPT序列同源的基序处发生重组的证据。CAB治疗下HIV的持续存在与LTR环序列的转录和重组有关。
