B-cell Tolerance and Humoral Immunity to HIV-1

只有在早期细胞免疫反应抑制HIV复制后才出现血清抗体反应，这导致人们对体液免疫在控制HIV感染中的重要性产生怀疑。尽管如此，罕见的，广泛的交叉反应性抗体能够在体外中和多种HIV-1分离株，并且当被动给予猴子时，可以预防SHIV的实验感染。为什么HIV感染者很少产生这种抗体？最近，这些罕见的HIV中和抗体中的几种显示出与自身抗原反应，导致有效的HIV体液应答受到也识别自身抗原的HIV反应性B细胞的耐受性限制的可能性。我们将检验这样的假设，即识别HIV-1 gp-41膜近端外部区（MPER）的遗传保守中和表位的B细胞存在于早期发育不成熟的B细胞中，但在其随后的发育/成熟过程中被耐受并丢失。

The emergence of serum antibody responses only after early cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered to monkeys, prevent experimental infection by SHIV. Why are such antibodies rarely produced by HIVinfected patients? Recently, several of these rare, HIV neutralizing antibodies were shown to react with self-antigens leading to the possibility that effective HIV humoral responses are constrained by the tolerization of HIV-reactive B cells that also recognize self-antigens. We shall test the hypothesis that B cells that recognize phylogenetically conserved, neutralizing epitopes of the HIV-1 gp-41 membrane proximal external region (MPER) are present in early, developmentally immature B cells but are tolerized and lost during their subsequent development/maturation.