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.

IMPORTANCE 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.

我们比较和对比了致病性（猪尾猕猴[PTMs]）和非致病性（非洲绿猴[AGMs]）SIVsab感染，以评估在猿猴（SIV）和人类免疫缺陷病毒（HIV）中观察到的B细胞功能障碍的重要性。感染。我们报告说，B细胞的丢失与致病性SIV感染特别相关，而在SIV不致病的自然宿主中，B细胞在淋巴结（LNs）和肠中均迅速增加。与病原性SIV感染相关的SIV相关B细胞功能异常的特征是幼稚B细胞丢失，由于其重新分布到肠道而导致的静息记忆B细胞丢失，激活的B细胞增加以及循环的组织样记忆B细胞增加，和B调节细胞（Bregs）的扩增。尽管在慢性病原性SIV感染过程中，循环中的B细胞实际上已恢复到感染前的水平，但恢复主要是由于“精疲力竭”的病毒特异性B细胞（即活化的记忆细胞和组织样记忆B细胞）的扩增所致。尽管存在B细胞功能障碍，但PTM中SIV特异性抗体（Ab）的产生要高于AGM中的警告，但需要注意的是PTM中疾病的快速发展与抗SIV Ab的缺乏密切相关。在致病性和非致病性感染之间，中和效价以及免疫应答的亲和力和成熟度没有区别，除了构象表位识别，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的模式与在HIV感染对象中观察到的那些更为相似，这表明天然宿主可能更适合于模拟旨在预防HIV疾病进展的免疫策略。致病性和非致病性感染之间在记忆B细胞亚群动力学方面的众多差异表明它们在HIV / SIV感染的发病机理中的作用，并表明监测B细胞可能是评估疾病进展的可靠方法。

重要性我们在这里报告说，HIV / SIV相关的B细胞功能障碍（定义为总B和记忆B细胞丢失，B调节细胞[Breg]计数增加以及B细胞激活和凋亡），与病原性SIV感染特别相关，在此过程中不存在天然非人类灵长类动物宿主中非致病性SIV感染的过程。B细胞群体的改变与中和抗体的产生无关，中和抗体的水平在两个物种中相似。快速进行性感染与SIV特异性抗体生产的严重损害有关。虽然我们没有发现病原性和非病原性SIV感染在亲和力和成熟度上有重大差异，但我们发现构象表位识别方面存在重大差异，非致病性感染的特征是从低构象到高构象的演变。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。