New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts, USA.
J Virol. 2013 Jul;87(13):7246-54. doi: 10.1128/JVI.00798-13. Epub 2013 May 1.
Vaccine/challenge experiments that utilize live attenuated strains of simian immunodeficiency virus (SIV) in monkeys may be useful for elucidating what is needed from a vaccine in order to achieve protective immunity. Derivatives of SIVmac239 and SIVmac239Δnef were constructed in which env sequences were replaced with those of the heterologous strain E543; these were then used in vaccine/challenge experiments. When challenge occurred at 22 weeks, 10 of 12 monkeys exhibited apparent sterilizing immunity despite a mismatch of Env sequences, compared to 12 of 12 monkeys with apparent sterilizing immunity when challenge virus was matched in its Env sequence. However, when challenge occurred at 6 weeks, 6 of 6 SIV239Δnef-immunized monkeys became superinfected by challenge virus mismatched in its Env sequence (SIV239/EnvE543). These results contrast markedly not only with the results of the week 22 challenge but also with the sterilizing immunity observed in 5 of 5 SIV239Δnef-immunized rhesus monkeys challenged at 5 weeks with SIV239, i.e., with no mismatch of Env sequences. We conclude from these studies that a mismatch of Env sequences in the challenge virus can have a dramatic effect on the extent of apparent sterilizing immunity when challenge occurs relatively early, 5 to 6 weeks after the nef-deleted SIV administration. However, by 22 weeks, mismatch of Env sequences has little or no influence on the degree of protection against challenge virus. Our findings suggest that anti-Env immune responses are a key component of the protective immunity elicited by live attenuated, nef-deleted SIV.
利用猴体中活的减毒猴免疫缺陷病毒（SIV）进行疫苗/攻毒实验，可能有助于阐明获得保护性免疫所需的疫苗条件。构建了 SIVmac239 和 SIVmac239Δnef 的衍生物，其中 env 序列被异源株 E543 的 env 序列取代；然后将其用于疫苗/攻毒实验。当在 22 周进行攻毒时，尽管Env 序列不匹配，12 只猴子中有 10 只表现出明显的绝育性免疫，而当攻毒病毒的 Env 序列匹配时，12 只猴子中有 12 只表现出明显的绝育性免疫。然而，当在 6 周进行攻毒时，6 只 SIV239Δnef 免疫的猴子被与其 Env 序列不匹配的攻毒病毒再次感染（SIV239/EnvE543）。这些结果不仅与 22 周攻毒的结果形成鲜明对比，而且与在 5 周用 SIV239 对 5 只 SIV239Δnef 免疫的恒河猴进行攻毒时观察到的绝育性免疫形成鲜明对比，即 Env 序列无不匹配。我们从这些研究中得出结论，当攻毒发生得相对较早（在 nef 缺失的 SIV 给药后 5 至 6 周）时，攻毒病毒中 Env 序列的不匹配会对明显的绝育性免疫的程度产生显著影响。然而，在 22 周时，Env 序列的不匹配对抵抗攻毒病毒的保护程度几乎没有影响。我们的发现表明，抗 Env 免疫反应是活的减毒、 nef 缺失的 SIV 引发的保护性免疫的关键组成部分。
