HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques
HIV DNA-Adenovirus Multiclade Envelope Vaccine Induces gp41 Antibody Immunodominance in Rhesus Macaques
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DOI：
10.1128/jvi.00923-17
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发表时间：
2017-11-01
影响因子：
5.4
通讯作者：
Haynes, Barton F.
中科院分区：
文献类型：
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作者：
Han, Qifeng;Williams, Wilton B.;Haynes, Barton F.
在HIV-1疫苗试验网络(HVTN)有效性试验505(HVTN 505)中研究的HIV-1多分支(A、B和C)包膜(Env)DNA/重组腺病毒5型(RAd5)疫苗的受试者的显性抗体反应以Env gp41为靶标并与微生物抗原发生交叉反应。在这项研究中，我们询问了DNA/rAd5疫苗是否在恒河猴(RMS)中诱导了类似的抗体反应，RMS通常被用作人类HIV-1感染和测试候选HIV-1疫苗的动物模型。我们还询问，在微生物定植的早期阶段，是否可以通过免疫新生儿RMS来避免gp41免疫优势。我们发现，DNA/rAd5疫苗在成人和新生儿RMS中诱发gp41反应性记忆B细胞的频率高于gp120记忆B细胞。对疫苗诱导的Env反应性B细胞库的分析表明，成人和新生儿RMS中的大多数HIV-1 Env反应性抗体都是针对gp41的。有趣的是，从RMS分离的gp41反应性抗体的子集与宿主抗原交叉反应，包括自体肠道微生物群。因此，在HVTN 505疫苗疗效试验中观察到，含有gp41的DNA/rAd5疫苗诱导了来自RMS中血液记忆B细胞的显性gp41微生物群交叉反应抗体。这些数据表明，RMS可用于研究候选HIV-1疫苗中gp41的免疫优势。此外，新生儿RMS的定植发生在出生的第一周，在此期间接种新生儿RMS也诱导了显性的gp41抗体反应。重要的是，我们的结果对于目前在HIV-1疫苗领域评估HIV-1环境gp140在RMS和人类中诱导的gp41免疫显性现象是至关重要的。我们的数据表明，RMS是研究这一现象并在新的HIV-1环境三聚体疫苗设计中确定免疫原性的合适动物模型。成人和新生儿RMS的记忆B细胞均显示gp41免疫优势，提示早期免疫不能克服gp41的显性反应。
Dominant antibody responses in vaccinees who received the HIV-1 multiclade (A, B, and C) envelope (Env) DNA/recombinant adenovirus virus type 5 (rAd5) vaccine studied in HIV-1 Vaccine Trials Network (HVTN) efficacy trial 505 (HVTN 505) targeted Env gp41 and cross-reacted with microbial antigens. In this study, we asked if the DNA/rAd5 vaccine induced a similar antibody response in rhesus macaques (RMs), which are commonly used as an animal model for human HIV-1 infections and for testing candidate HIV-1 vaccines. We also asked if gp41 immunodominance could be avoided by immunization of neonatal RMs during the early stages of microbial colonization. We found that the DNA/rAd5 vaccine elicited a higher frequency of gp41-reactive memory B cells than gp120-memory B cells in adult and neonatal RMs. Analysis of the vaccine-induced Env-reactive B cell repertoire revealed that the majority of HIV-1 Env-reactive antibodies in both adult and neonatal RMs were targeted to gp41. Interestingly, a subset of gp41-reactive antibodies isolated from RMs cross-reacted with host antigens, including autologous intestinal microbiota. Thus, gp41-containing DNA/rAd5 vaccine induced dominant gp41-microbiota cross-reactive antibodies derived from blood memory B cells in RMs as observed in the HVTN 505 vaccine efficacy trial. These data demonstrated that RMs can be used to investigate gp41 immunodominance in candidate HIV-1 vaccines. Moreover, colonization of neonatal RMs occurred within the first week of life, and immunization of neonatal RMs during this time also induced a dominant gp41-reactive antibody response.IMPORTANCE Our results are critical to current work in the HIV-1 vaccine field evaluating the phenomenon of gp41 immunodominance induced by HIV-1 Env gp140 in RMs and humans. Our data demonstrate that RMs are an appropriate animal model to study this phenomenon and to determine the immunogenicity in new HIV-1 Env trimer vaccine designs. The demonstration of gp41 immunodominance in memory B cells of both adult and neonatal RMs indicated that early vaccination could not overcome gp41 dominant responses.