CD4⁺ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4⁺ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4⁺ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8⁺ T cells as well. In this review, we discuss what is known about CD4⁺ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host–pathogen interaction.

CD4 ⁺ T细胞在急性期对慢性病毒感染的反应以及一旦建立慢性感染后对感染的部分遏制起着至关重要的作用。随着感染的持续，病毒特异性CD4 ⁺ T细胞反应的表型开始发生变化。在小鼠和人类的慢性病毒感染研究中描述的主要变化是可检测的T辅助型（Th）1反应的降低。Th1的某些损失是由于在慢性抗原暴露的情况下增殖潜能降低和细胞因子生成降低所致。但是，最近的数据表明，Th1功能障碍伴随着病毒特异性CD4 ⁺的分化途径的转变T细胞，具有T滤泡辅助细胞（Tfh）表型的细胞富集。现在已经在病毒特异性CD8 ⁺ T细胞中鉴定出了一种在慢性感染过程中类似Tfh的程序。在本文中，我们讨论了关于慢性病毒感染中CD4 ⁺ T细胞分化的知识，重点是Tfh程序的出现以及这种转变对Tfh功能和宿主-病原体相互作用的影响。