Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time.
Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time.
复制标题
来自未经治疗的患者的 HIV-1 CRF07_BC 的中和敏感性，重点关注随时间的演变
DOI：
10.3389/fcimb.2022.862754
复制
发表时间：
2022
影响因子：
5.7
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Wang L;Liang S;Huang J;Ding Y;He L;Hao Y;Ren L;Zhu M;Feng Y;Rashid A;Liu Y;Jiang S;Hong K;Ma L
HIV-1包膜（Env）糖蛋白的多样性影响了广泛中和抗体（bNAb）的效力和广度，bNAb是预防和治疗HIV-1感染的抗逆转录病毒药物的有前途的替代品。为了促进免疫原设计和治疗性中和抗体的开发，我们表征了病毒进化，并监测了HIV-1 CRF07_BC感染的长期非进展患者的中和活性/敏感性变化。59个全长Env基因片段来自2016年至2020年期间从患者中连续采集的4份血浆样本。患者来源的Env基因测序显示，V1和V5中的潜在N-连接糖基化位点（PNGS）随时间显著增加。此外，基于Env基因序列产生了24种功能性Env假型病毒。虽然所有24种Env假型病毒对同时和随后的自体血浆以及bNAb（包括10 E8、VRC 01和12 A21）保持敏感，但对应于较晚采样时间的Env假型病毒对自体血浆和bNAb的耐药性越来越强。所有24种Env假型病毒对bNAb 2G 12、PGT 121和PGT 135具有抗性。相对于全球HIV-1参考样本组，所有4份连续样本的血浆中和幅度均为100%。免疫逃逸突变体导致对不同表位的bNAb靶向的抗性增加。我们的研究确定了gp 41中已知的突变F277 W和V5中先前未表征的突变S465 T，这可能与病毒对bNAb的耐药性增加有关。
The diversity of HIV-1 envelope (Env) glycoproteins affects the potency and breadth of broadly neutralizing antibodies (bNAbs), a promising alternative to antiretroviral drugs for the prevention and treatment of HIV-1 infection. To facilitate immunogen design and development of therapeutic neutralizing antibodies, we characterized viral evolution and monitored the changes in neutralizing activity/sensitivity of a long-term non-progressor patient with HIV-1 CRF07_BC infection. Fifty-nine full-length Env gene fragments were derived from four plasma samples sequentially harvested from the patient between 2016 and 2020. Sequencing of patient-derived Env genes revealed that potential N-linked glycosylation sites (PNGS) in V1 and V5 significantly increased over time. Further, 24 functional Env-pseudotyped viruses were generated based on Env gene sequences. While all 24 Env-pseudotyped viruses remained sensitive to concurrent and subsequent autologous plasma, as well as bNAbs, including 10E8, VRC01, and 12A21, Env-pseudotyped viruses corresponding to later sampling time were increasingly more resistant to autologous plasma and bNAbs. All 24 Env-pseudotyped viruses were resistant to bNAbs 2G12, PGT121, and PGT135. The neutralization breadth of plasma from all four sequential samples was 100% against the global HIV-1 reference panel. Immune escape mutants resulted in increased resistance to bNAb targeting of different epitopes. Our study identified known mutations F277W in gp41 and previously uncharacterized mutation S465T in V5 which may be associated with increased viral resistance to bNAbs.