CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell <i>trans</i>-infection

HIV-1 frequently escapes from CD8 T cell responses via HLA-I restricted adaptation, leading to the accumulation of adapted epitopes (AE). We previously demonstrated that AE compromise CD8 T cell responses during acute infection and are associated with poor clinical outcomes. Here, we examined the impact of AE on CD8 T cell responses and their biological relevance in chronic HIV infection (CHI). In contrast to acute infection, the majority of AE are immunogenic in CHI. Longitudinal analyses from acute to CHI showed an increased frequency and magnitude of AE-specific IFNγ responses compared to NAE-specific ones. These AE-specific CD8 T cells also were more cytotoxic to CD4 T cells. In addition, AE-specific CD8 T cells expressed lower levels of PD1 and CD57, as well as higher levels of CD28, suggesting a more activated and less exhausted phenotype. During CHI, viral sequencing identified AE-encoding strains as the dominant quasispecies. Despite increased CD4 T cell cytotoxicity, CD8 T cells responding to AE promoted dendritic cell (DC) maturation and CD4 T cell trans-infection perhaps explaining why AE are predominant in CHI. Taken together, our data suggests that the emergence of AE-specific CD8 T cell responses in CHI confers a selective advantage to the virus by promoting DC-mediated CD4 T cell trans-infection.人类免疫缺陷病毒1型（HIV-1）可通过HLA-I限制性适配（HLA-I restricted adaptation）逃逸CD8阳性T细胞免疫应答，进而导致适配表位（adapted epitopes，AE）的积累。我们此前已证实，适配表位会在急性感染期间削弱CD8阳性T细胞应答，并与不良临床转归相关。本研究探讨了适配表位对慢性HIV感染（CHI）中CD8阳性T细胞应答的影响及其生物学意义。与急性感染不同，慢性HIV感染中多数适配表位具有免疫原性。从急性感染至慢性HIV感染的纵向分析显示，相较于未适配表位（non-adapted epitopes，NAE）特异性应答，适配表位特异性干扰素γ（IFNγ）应答的频率与强度均显著升高。此类适配表位特异性CD8阳性T细胞对CD4阳性T细胞的细胞毒性也更强。此外，适配表位特异性CD8阳性T细胞的PD-1与CD57表达水平更低，而CD28表达水平更高，提示其表型更为活化且耗竭程度更低。在慢性HIV感染期间，病毒测序结果显示，编码适配表位的毒株为优势准种。尽管适配表位特异性CD8阳性T细胞对CD4阳性T细胞的细胞毒性有所增强，但其能够促进树突状细胞（DC）成熟与CD4阳性T细胞转感染（trans-infection），这或许可解释为何适配表位在慢性HIV感染中占据主导地位。综上，本研究数据表明，慢性HIV感染中出现的适配表位特异性CD8阳性T细胞应答，可通过树突状细胞介导的CD4阳性T细胞转感染，为病毒提供选择优势。