B-cell Tolerance and Humoral Immunity to HIV-1

在早期细胞免疫反应抑制了HIV复制之后才出现血清抗体反应，这使人们对体液免疫在控制HIV感染中的重要性产生了怀疑。尽管如此，罕见的、广泛交叉反应的抗体能够在体外中和多种HIV-1分离株，并且当被动地给予猴子时，可以防止实验性的SHIV感染。为什么艾滋病毒感染者很少产生这种抗体？最近，一些罕见的HIV中和抗体被证明与自身抗原反应，导致有效的HIV体液反应可能受到同样识别自身抗原的HIV反应性B细胞的耐受性的限制。我们将验证这样一种假设，即B细胞能够识别在系统发育上保守的、中和的HIV-1 gp-41膜近外区（MPER）表位存在于早期发育不成熟的B细胞中，但在随后的发育/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.