Escape mechanisms of HIV-1 from HIV-1-specific CTLs

众所周知，人类白细胞抗原-B^*57/58、-B^*27和-B*51等位基因与艾滋病的缓慢进展有关，但这些等位基因所限制的细胞毒性T淋巴细胞(CTL)在HIV-1长期控制中的作用仍不清楚。我们研究了携带人类白细胞抗原B^*5101的长期非进展型(LTNP)和进展缓慢(慢进型)血友病患者中HIV-1特异性CTL。在LTNPs中同时检测到Pol283-8和Pol743-9特异的CTL，它们在体外都有很强的抑制HIV-1复制的能力，而在进展缓慢的人中只检测到Pol743-9特异的CTL。LTNPs具有HIV-1在这些表位上的野生型序列或突变，降低了特定CTL抑制HIV-1复制和病毒适合性的能力。相比之下，进展缓慢的人和进步的人携带的HIV-1带有逃逸突变，不会影响病毒的适合性。对一例血友病患者的纵向分析证实，Pol283-8逃逸突变的出现与高病毒载量之间存在关联。诱导具有较强抑制HIV-1复制能力的HIV-1特异性CTL，并进化为病毒适合性和T细胞识别能力降低的突变株，被发现对HIV-1的控制大约25年是必要的。

It is well known that HLA-B^*57/58, -B^*27, and -B*^51 alleles are associated with slow disease progression to AIDS, but the role of cytotoxic T lymphocytes(CTLs)restricted by these alleles in long-term control of HIV-1 still remains unknown. We investigated HIV-1-specific CTLs in long-term non-progressing(LTNP)and slow-progressing(slow progressors)hemophiliacs carrying HLA-B^*5101. Both Pol283-8-specific and Pol743-9-specific CTLs, which have a strong ability to suppress HIV-1 replication in vitro, were detected in LTNPs whereas only Pol743-9-specific CTLs were found in the slow progressors. The LTNPs had HIV-1 possessing wild-type sequence in these epitopes or a mutation reducing the ability of the specific CTLs to suppress HIV-1 replication and viral fitness. In contrast, the slow progressors and progressors had HIV-1 with escape mutations that did not influence viral fitness. Longitudinal analysis of a hemophiliac confirmed the association between the appearance of a Pol283-8 escape mutant and a high viral load. The induction of HIV-1-specific CTLs with a strong ability to suppress HIV-1 replication and the evolution to a mutant with reduced viral fitness and T cell recognition were found to be necessary for the control of HIV-1 for approximately 25 years.