PDF(Pubmed)
Abstract：
UNASSIGNED: Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs.
UNASSIGNED: We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.
UNASSIGNED: Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.
UNASSIGNED: Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.
UNASSIGNED: We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation.
UNASSIGNED: Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir.
UNASSIGNED: Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.
摘要：
■在静息的CD4T细胞和其他细胞亚群中持续存在的HIV储库病毒是治愈努力的主要障碍。在某些情况下，通过早期启动加强抗逆转录病毒疗法（ART）可以实现治疗后的病毒控制，但其潜在机制尚未完全了解。我们假设在感染高峰之前的超急性期开始ART会影响大小，HIV-1C亚型病毒库的衰变动力学和景观特征。
■我们研究了来自德班的35名感染高危女性，南非通过每周两次检测血浆HIV-1RNA来确定患有超急性HIV感染。研究参与者包括11人，他们在病毒血症（DPOV）发作后的中位数456（297-1203）天开始ART，和24名开始ART的中位数为1（1-3）DPOV。我们使用外周血单核细胞（PBMC）通过ddPCR测量总HIV-1DNA，并通过全长个体前病毒测序（FLIP-seq）对水库病毒基因组进行测序，从检测HIV开始到治疗开始后1年。
■与未经治疗的个体相比，超急性感染中的ART使病毒血症高峰减弱（p<0.0001），同期测量的HIV-1总DNA没有差异(p=0.104).在接受ART治疗1年以上的早期患者中，总HIVDNA稳步下降（p=0.0004），在晚期治疗组中没有观察到显著变化。治疗一年后，早期治疗组的总HIV-1DNA低于晚期治疗组（p=0.02）。697个单病毒基因组序列的产生揭示了纵向前病毒遗传景观在一年内的差异，后期治疗,和早期治疗的感染：1年后，未经治疗的感染（31％）中完整基因组对HIV-1DNA总库的相对贡献高于晚期治疗（14％）和早期治疗的感染（0％）。在晚期和早期感染中开始的治疗导致完整病毒基因组（每月13％和51％）相对于缺陷病毒基因组（每月2％和35％）的更快衰减。然而,与不再检测到完整基因组的早期治疗相反，在慢性治疗开始后一年仍观察到完整基因组。此外，早期ART降低了完整基因组的系统发育多样性，并限制了细胞毒性T淋巴细胞免疫逃逸变体在水库中的接种和持久性。
■总的来说，我们的结果表明，尽管ART在超急性HIV-1亚型C感染中开始并不影响水库播种，然而，它与完整病毒基因组更快速的衰变有关，降低遗传复杂性和水库中的免疫逃逸，与其他介入策略相结合可以加速储层清除。
■我们研究了来自德班的35名感染高危女性，南非通过每周两次检测血浆HIV-1RNA来确定患有超急性HIV感染。研究参与者包括11人，他们在病毒血症（DPOV）发作后的中位数456（297-1203）天开始ART，和24名开始ART的中位数为1（1-3）DPOV。我们使用外周血单核细胞（PBMC）通过ddPCR测量总HIV-1DNA，并通过全长个体前病毒测序（FLIP-seq）对水库病毒基因组进行测序，从检测HIV开始到治疗开始后1年。
■与未经治疗的个体相比，超急性感染中的ART使病毒血症高峰减弱（p<0.0001），同期测量的HIV-1总DNA没有差异(p=0.104).在接受ART治疗1年以上的早期患者中，总HIVDNA稳步下降（p=0.0004），在晚期治疗组中没有观察到显著变化。治疗一年后，早期治疗组的总HIV-1DNA低于晚期治疗组（p=0.02）。697个单病毒基因组序列的产生揭示了纵向前病毒遗传景观在一年内的差异，后期治疗,和早期治疗的感染：1年后，未经治疗的感染（31％）中完整基因组对HIV-1DNA总库的相对贡献高于晚期治疗（14％）和早期治疗的感染（0％）。在晚期和早期感染中开始的治疗导致完整病毒基因组（每月13％和51％）相对于缺陷病毒基因组（每月2％和35％）的更快衰减。然而,与不再检测到完整基因组的早期治疗相反，在慢性治疗开始后一年仍观察到完整基因组。此外，早期ART降低了完整基因组的系统发育多样性，并限制了细胞毒性T淋巴细胞免疫逃逸变体在水库中的接种和持久性。
■总的来说，我们的结果表明，尽管ART在超急性HIV-1亚型C感染中开始并不影响水库播种，然而，它与完整病毒基因组更快速的衰变有关，降低遗传复杂性和水库中的免疫逃逸，与其他介入策略相结合可以加速储层清除。
