Muir Roshell, Metcalf Talibah, Tardif Virginie, Takata Hiroshi, Phanuphak Nittaya, Kroon Eugene, Colby Donn J, Trichavaroj Rapee, Valcour Victor, Robb Merlin L, Michael Nelson L, Ananworanich Jintanat, Trautmann Lydie, Haddad Elias K
Drexel University, Department of Medicine, Division of Infectious Diseases & HIV Medicine, Philadelphia, Pennsylvania, United States of America.
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, United States of America.
PLoS Pathog. 2016 Jul 27;12(7):e1005777. doi: 10.1371/journal.ppat.1005777. eCollection 2016 Jul.
The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory.
HIV感染的极早期急性(4期1和2阶段)(1/2阶段)和晚期急性(4期3阶段)(3阶段)个体的RV254队列被用于研究急性HIV感染中的辅助性T细胞- B细胞反应以及早期抗逆转录病毒治疗(ART)对T细胞和B细胞功能的影响。为了研究这一点,检测了该队列中循环滤泡辅助性T细胞(cTfh)的功能,并对cTfh和记忆B细胞群体进行了表型分析。与1/2阶段相比,在3阶段接受治疗的个体中观察到cTfh细胞功能受损。与1/2阶段相比,cTfh/B细胞共培养在3阶段显示出更低的B细胞存活率和IgG分泌。这与更低的IL-10以及升高的RANTES和TNF-α同时出现,提示炎症在改变cTfh和B细胞反应中发挥作用。发现3阶段血浆病毒载量升高与cTfh介导的B细胞IgG产生减少相关,表明病毒血症增加在cTfh损伤和体液反应功能失调中起作用。在成熟B细胞区室中也明显存在表型扰动,最显著的是与1/2阶段相比,3阶段静息记忆B细胞减少,这与更高的病毒血症同时出现。我们的共培养试验还表明,尽管程度较低,但内在的记忆B细胞缺陷可能导致反应受损。总体而言,与1/2阶段相比,3阶段cTfh介导的B细胞反应显著改变,同时炎症增加且记忆B细胞减少。这些数据表明,对急性HIV感染个体进行早期ART可以预防免疫失调,同时保留cTfh功能和B细胞记忆。
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