Department of Pathology, University of Miami, Miami, Florida, USA
Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
J Virol. 2018 Jul 31;92(16). doi: 10.1128/JVI.00690-18. Print 2018 Aug 15.
Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Approximately 21% of and 50% of RMs control chronic-phase viremia after SIVmac239 infection. Because CD8 T cells targeting Mamu-B08-restricted SIV epitopes have been implicated in virologic suppression in RMs, we investigated whether this might also be true for RMs. Two groups of RMs were vaccinated with genes encoding Mamu-B17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike RMs, preexisting SIV-specific CD8 T cells alone do not facilitate long-term virologic suppression in RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection. A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele Approximately 21% of macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8 T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with (group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8 T cells for virologic control in macaques and implicate anti-Env antibodies in containment of SIV infection.
某些主要组织相容性复合体 I 类（MHC-I）等位基因与人类免疫缺陷病毒（HIV）感染人群和感染猴免疫缺陷病毒（SIV）的恒河猴（RMs）中病毒复制的自发控制有关。这些 HIV/SIV 复制的“精英”控制的情况通常是免疫介导的，从而为研究抗慢病毒免疫提供了框架。在这项研究中，我们研究了疫苗接种如何影响表达 MHC-I 等位基因的 SIV 复制 大约 21%的 和 50%的 RM 在 SIVmac239 感染后控制慢性期病毒血症。因为针对 Mamu-B08 限制性 SIV 表位的 CD8 T 细胞已被牵连到 RM 中的病毒学抑制中，所以我们研究了这是否也适用于 RM。两组 RM 接种了编码 Vif 和 Nef 中 Mamu-B17 限制性表位的基因。这些基因单独传递（第 1 组）或与 一起传递（第 2 组）。第 3 组包括 MHC-I 匹配的 RM，作为对照组。令人惊讶的是，与第 3 组相比，第 1 组疫苗方案对病毒复制的影响很小，这表明与 RM 不同，单独存在的针对 SIV 的 CD8 T 细胞本身并不能促进 RM 中的长期病毒学抑制。然而，令人瞩目的是，第 2 组中有 5/8 的疫苗接种者在感染后不久就将病毒血症控制在<15 个病毒 RNA 拷贝/ml 以下。第 2 组未检测到针对 SIVmac239 的血清中和活性，尽管疫苗诱导的 gp140 结合抗体与病毒载量的最低点呈负相关。总的来说，这些数据为 RM 中的精英控制的独特机制提供了新的见解，并表明疫苗诱导的非中和性抗 Env 抗体在控制免疫缺陷病毒感染中起作用。对 HIV 保护性免疫相关因素的更好理解可能有助于预防性疫苗的开发。因此，我们研究了在表达主要组织相容性复合体 I 类等位基因 大约 21%的 RM 中，SIV 感染的结果，这些 RM 在 SIV 感染后自发控制慢性期病毒血症，这一效应可能涉及针对 Mamu-B*17 限制性 SIV 表位的 CD8 T 细胞。我们单独用编码 Vif 和 Nef 中免疫显性表位的基因（第 1 组）或与 一起接种（第 2 组）RM。尽管两种疫苗方案都不能预防 SIV 感染，但第 2 组中有 5/8 的疫苗接种者在感染后不久就将病毒血症控制在检测限以下。这种在第 1 组中未观察到的结果与疫苗诱导的非中和性 Env 结合抗体有关。这些发现表明，Vif 和 Nef 特异性 CD8 T 细胞对 RM 中的病毒学控制的贡献有限，并暗示抗 Env 抗体在 SIV 感染的控制中起作用。
