Brocca-Cofano Egidio, Kuhrt David, Siewe Basile, Xu Cuiling, Haret-Richter George S, Craigo Jodi, Labranche Celia, Montefiori David C, Landay Alan, Apetrei Cristian, Pandrea Ivona
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Virol. 2017 Nov 14;91(23). doi: 10.1128/JVI.01051-17. Print 2017 Dec 1.
We compared and contrasted pathogenic (in pig-tailed macaques [PTMs]) and nonpathogenic (in African green monkeys [AGMs]) SIVsab infections to assess the significance of the B cell dysfunction observed in simian (SIV) and human immunodeficiency virus (HIV) infections. We report that the loss of B cells is specifically associated with the pathogenic SIV infection, while in the natural hosts, in which SIV is nonpathogenic, B cells rapidly increase in both lymph nodes (LNs) and intestine. SIV-associated B cell dysfunction associated with the pathogenic SIV infection is characterized by loss of naive B cells, loss of resting memory B cells due to their redistribution to the gut, increases of the activated B cells and circulating tissue-like memory B cells, and expansion of the B regulatory cells (Bregs). While circulating B cells are virtually restored to preinfection levels during the chronic pathogenic SIV infection, restoration is mainly due to an expansion of the "exhausted," virus-specific B cells, i.e., activated memory cells and tissue-like memory B cells. Despite of the B cell dysfunction, SIV-specific antibody (Ab) production was higher in the PTMs than in AGMs, with the caveat that rapid disease progression in PTMs was strongly associated with lack of anti-SIV Ab. Neutralization titers and the avidity and maturation of immune responses did not differ between pathogenic and nonpathogenic infections, with the exception of the conformational epitope recognition, which evolved from low to high conformations in the natural host. The patterns of humoral immune responses in the natural host are therefore more similar to those observed in HIV-infected subjects, suggesting that natural hosts may be more appropriate for modeling the immunization strategies aimed at preventing HIV disease progression. The numerous differences between the pathogenic and nonpathogenic infections with regard to dynamics of the memory B cell subsets point to their role in the pathogenesis of HIV/SIV infections and suggest that monitoring B cells may be a reliable approach for assessing disease progression. We report here that the HIV/SIV-associated B cell dysfunction (defined by loss of total and memory B cells, increased B regulatory cell [Breg] counts, and B cell activation and apoptosis) is specifically associated with pathogenic SIV infection and absent during the course of nonpathogenic SIV infection in natural nonhuman primate hosts. Alterations of the B cell population are not correlated with production of neutralizing antibodies, the levels of which are similar in the two species. Rapid progressive infections are associated with a severe impairment in SIV-specific antibody production. While we did not find major differences in avidity and maturation between the pathogenic and nonpathogenic SIV infections, we identified a major difference in conformational epitope recognition, with the nonpathogenic infection being characterized by an evolution from low to high conformations. B cell dysfunction should be considered in designing immunization strategies aimed at preventing HIV disease progression.
我们比较并对比了致病性SIVsab感染（在食蟹猴[PTMs]中）和非致病性SIVsab感染（在非洲绿猴[AGMs]中），以评估在猿猴免疫缺陷病毒（SIV）和人类免疫缺陷病毒（HIV）感染中观察到的B细胞功能障碍的意义。我们报告称，B细胞的丧失与致病性SIV感染特异性相关，而在SIV无致病性的天然宿主中，B细胞在淋巴结（LNs）和肠道中均迅速增加。与致病性SIV感染相关的SIV诱导的B细胞功能障碍的特征是幼稚B细胞丧失、静息记忆B细胞因重新分布到肠道而丧失、活化B细胞和循环组织样记忆B细胞增加以及B调节细胞（Bregs）扩增。虽然在慢性致病性SIV感染期间循环B细胞实际上恢复到感染前水平，但恢复主要是由于“耗竭的”、病毒特异性B细胞的扩增，即活化记忆细胞和组织样记忆B细胞。尽管存在B细胞功能障碍，但食蟹猴中SIV特异性抗体（Ab）的产生高于非洲绿猴，不过食蟹猴中疾病的快速进展与缺乏抗SIV抗体密切相关。中和滴度以及免疫反应的亲和力和成熟度在致病性和非致病性感染之间没有差异，但构象表位识别除外，其在天然宿主中从低构象演变为高构象。因此，天然宿主中的体液免疫反应模式与HIV感染受试者中观察到的模式更相似，这表明天然宿主可能更适合用于模拟旨在预防HIV疾病进展的免疫策略。致病性和非致病性感染在记忆B细胞亚群动态方面的众多差异表明它们在HIV/SIV感染发病机制中的作用，并表明监测B细胞可能是评估疾病进展的可靠方法。我们在此报告，HIV/SIV相关的B细胞功能障碍（由总B细胞和记忆B细胞丧失、B调节细胞[Breg]计数增加以及B细胞活化和凋亡定义）与致病性SIV感染特异性相关，在天然非人灵长类宿主的非致病性SIV感染过程中不存在。B细胞群体的改变与中和抗体的产生无关，中和抗体水平在这两个物种中相似。快速进展性感染与SIV特异性抗体产生的严重受损相关。虽然我们在致病性和非致病性SIV感染之间未发现亲和力和成熟度的主要差异，但我们确定了构象表位识别方面的一个主要差异，非致病性感染的特征是从低构象演变为高构象。在设计旨在预防HIV疾病进展的免疫策略时应考虑B细胞功能障碍。
