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

众所周知，HLA-B^*57/58、-B^*27和-B*^51等位基因与艾滋病的缓慢疾病进展相关，但受这些等位基因限制的细胞毒性T淋巴细胞（CTL）在长期控制HIV-1中的作用仍不清楚。我们研究了携带HLA-B^*5101的长期非进展（LTNP）和缓慢进展（缓慢进展者）血友病患者中的HIV-1特异性CTL。在LTNP中检测到Pol 283 -8特异性和Pol 743 -9特异性CTL，它们具有很强的体外抑制HIV-1复制的能力，而在缓慢进展者中仅发现Pol 743 -9特异性CTL。LTNP具有在这些表位中具有野生型序列的HIV-1或降低特异性CTL抑制HIV-1复制和病毒适应性的能力的突变。相比之下，缓慢进展者和进展者的HIV-1逃逸突变不影响病毒适应性。对血友病患者的纵向分析证实了Pol 283 -8逃逸突变体的出现与高病毒载量之间的关联。诱导HIV-1特异性CTL具有很强的抑制HIV-1复制的能力，并进化为病毒适应性和T细胞识别能力降低的突变体，被发现是控制HIV-1大约25年所必需的。

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.