California National Primate Research Center, University of California, Davis, CA, USA.
Vaccine. 2011 Apr 12;29(17):3124-37. doi: 10.1016/j.vaccine.2011.02.051. Epub 2011 Mar 4.
Despite antiretroviral medications, the rate of pediatric HIV-1 infections through breast-milk transmission has been staggering in developing countries. Therefore, the development of a vaccine to protect vulnerable infant populations should be actively pursued. We previously demonstrated that oral immunization of newborn macaques with vesicular stomatitis virus expressing simian immunodeficiency virus genes (VSV-SIV) followed 2 weeks later by an intramuscular boost with modified vaccinia ankara virus expressing SIV (MVA-SIV) successfully induced SIV-specific T and B cell responses in multiple lymphoid tissues, including the tonsil and intestine [13]. In the current study, we tested the oral VSV-SIV prime/systemic MVA-SIV boost vaccine for efficacy against multiple oral SIVmac251 challenges starting two weeks after the booster vaccination. The vaccine did not prevent SIV infection. However, in vaccinated infants, the level of SIV-specific plasma IgA (but not IgG) at the time of challenge was inversely correlated with peak viremia. In addition, the levels of SIV-specific IgA in saliva and plasma were inversely correlated with viral load at euthanasia. Animals with tonsils that contained higher frequencies of SIV-specific TNF-α- or IFN-γ-producing CD8(+) T cells and central memory T cells at euthanasia also had lower viremia. Interestingly, a marked depletion of CD25(+)FoxP3(+)CD4(+) T cells was observed in the tonsils as well as the intestine of these animals, implying that T regulatory cells may be a major target of SIV infection in infant macaques. Overall, the data suggest that, in infant macaques orally infected with SIV, the co-induction of local antiviral cytotoxic T cells and T regulatory cells that promote the development of IgA responses may result in better control of viral replication. Thus, future vaccination efforts should be directed towards induction of IgA and mucosal T cell responses to prevent or reduce virus replication in infants.
尽管有抗逆转录病毒药物，发展中国家通过母乳传播导致儿童 HIV-1 感染的比率仍然惊人。因此，积极开发一种疫苗来保护易受感染的婴儿群体是当务之急。我们之前的研究表明，用表达猿猴免疫缺陷病毒基因的水疱性口炎病毒（VSV-SIV）对新生恒河猴进行口服免疫，两周后用表达 SIV 的改良安卡拉痘苗病毒（MVA-SIV）进行肌肉内加强免疫，可成功诱导多个淋巴组织（包括扁桃体和肠道）中的 SIV 特异性 T 和 B 细胞反应[13]。在目前的研究中，我们测试了口服 VSV-SIV 初免/系统 MVA-SIV 加强疫苗对多次口服 SIVmac251 挑战的功效，从加强免疫后两周开始。该疫苗不能预防 SIV 感染。然而，在接种疫苗的婴儿中，挑战时 SIV 特异性血浆 IgA（但不是 IgG）的水平与峰值病毒血症呈反比。此外，唾液和血浆中的 SIV 特异性 IgA 水平与安乐死时的病毒载量呈反比。安乐死时扁桃体中含有更高频率的 SIV 特异性 TNF-α-或 IFN-γ 产生的 CD8(+)T 细胞和中央记忆 T 细胞的动物，其病毒血症也较低。有趣的是，这些动物的扁桃体和肠道中观察到 CD25(+)FoxP3(+)CD4(+)T 细胞明显耗竭，这表明 T 调节细胞可能是婴儿恒河猴中 SIV 感染的主要靶标。总的来说，这些数据表明，在婴儿恒河猴经口感染 SIV 后，局部抗病毒细胞毒性 T 细胞和促进 IgA 反应发展的 T 调节细胞的共同诱导可能导致病毒复制得到更好的控制。因此，未来的疫苗接种工作应致力于诱导 IgA 和黏膜 T 细胞反应，以防止或减少婴儿中的病毒复制。
