National Cancer Institute, Vaccine Branch, Bethesda, MD 20892, USA.
Vaccine. 2011 Aug 11;29(35):6017-28. doi: 10.1016/j.vaccine.2011.06.032. Epub 2011 Jun 25.
It has been proposed that microbial translocation might play a role in chronic immune activation during HIV/SIV infection. Key roles in fighting bacterial and fungal infections have been attributed to Th17 and Tc17 cells. Th17 cells can be infected with HIV/SIV, however whether effective vaccination leads to their maintenance following viral challenge has not been addressed. Here we retrospectively investigated if a vaccine regimen that potently reduced viremia post-challenge preserved Th17 and Tc17 cells, thus adding benefit in the absence of sterilizing protection. Rhesus macaques were previously vaccinated with replication-competent Adenovirus recombinants expressing HIVtat and HIVenv followed by Tat and gp140 protein boosting. Upon SHIV(89.6P) challenge, the vaccines exhibited a significant 4 log reduction in chronic viremia compared to sham vaccinated controls which rapidly progressed to AIDS [39]. Plasma and cryopreserved PBMC samples were examined pre-challenge and during acute and chronic infection. Control macaques exhibited a rapid loss of CD4(+) cells, including Th17 cells. Tc17 cells tended to decline over the course of infection although significance was not reached. Immune activation, assessed by Ki-67 expression, was associated with elevated chronic viremia of the controls. Significantly increased plasma IFN-γ levels were also observed. No increase in plasma LPS levels were observed suggesting a lack of microbial translocation. In contrast, vaccinated macaques had no evidence of immune activation within the chronic phase and preserved both CD4(+) T-cells and Tc17 cells in PBMC. Nevertheless, they exhibited a gradual, significant loss of Th17 cells which concomitantly displayed significantly higher CCR6 expression over time. The gradual Th17 cell decline may reflect mucosal homing to inflammatory sites and/or slow depletion due to ongoing low levels of SHIV replication. Our results suggest that potent viremia reduction during chronic SHIV infection will delay but not prevent the loss of Th17 cells.
有人提出，微生物易位可能在 HIV/SIV 感染期间慢性免疫激活中发挥作用。Th17 和 Tc17 细胞在对抗细菌和真菌感染中起着关键作用。Th17 细胞可以感染 HIV/SIV，但是有效的疫苗接种是否会在病毒攻击后维持它们的存在尚未得到解决。在这里，我们回顾性地研究了一种疫苗方案，该方案在挑战后强有力地降低了病毒血症，从而在没有杀菌保护的情况下增加了益处。以前，恒河猴用复制能力强的腺病毒重组体接种疫苗，表达 HIVtat 和 HIVenv，然后用 Tat 和 gp140 蛋白进行加强。在接受 SHIV(89.6P)挑战后，与假疫苗接种对照相比，疫苗在慢性病毒血症中表现出显著的 4 对数减少，而对照迅速进展为艾滋病[39]。在挑战前、急性和慢性感染期间检查了血浆和冷冻 PBMC 样本。对照猕猴表现出 CD4(+)细胞的迅速减少，包括 Th17 细胞。Tc17 细胞在感染过程中趋于下降，尽管未达到统计学意义。通过 Ki-67 表达评估的免疫激活与对照的慢性高病毒血症有关。还观察到显著增加的血浆 IFN-γ水平。未观察到血浆 LPS 水平增加，表明不存在微生物易位。相比之下，接种疫苗的猕猴在慢性期没有表现出免疫激活的迹象，并在 PBMC 中保留了 CD4(+)T 细胞和 Tc17 细胞。然而，它们表现出 Th17 细胞逐渐显著减少，同时随着时间的推移，CCR6 表达显著增加。Th17 细胞的逐渐减少可能反映了粘膜向炎症部位的归巢和/或由于持续的低水平 SHIV 复制而缓慢消耗。我们的结果表明，在慢性 SHIV 感染期间强有力地降低病毒血症将延迟但不能阻止 Th17 细胞的丢失。
